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Papers by David Anthony Lawrence

Research paper thumbnail of Wheeze and Food Allergies in Children Born via Cesarean Delivery

American Journal of Epidemiology, 2018

We examined whether cesarean delivery (CD) increased the risk of wheeze or food allergy in early ... more We examined whether cesarean delivery (CD) increased the risk of wheeze or food allergy in early childhood compared with vaginal delivery and whether these associations were mediated by breastfeeding. The study population was the Upstate KIDS cohort (2008-2010) of mothers and infants from the State of New York (excluding New York City). Infant's wheeze was reported by questionnaire every 4-6 months until 3 years of age, as were food allergies beginning at 8 months. Modified Poisson regression was used to compare risks of the outcomes according to mode of delivery (MOD). Potential confounders were identified a priori using directed acyclic graphs. Emergency CD (n = 1,356) was associated with elevated risk of wheeze, adjusting for pregnancy complications, maternal atopy, gestational age, birth weight, and smoking during pregnancy (risk ratio = 2.47, 95% confidence interval: 1.31, 4.66), and an increased risk of food allergy, adjusting for maternal atopy, prepregnancy body mass index, smoking during pregnancy, and parity (risk ratio = 3.02, 95% confidence interval: 1.26, 7.25). Neither outcome was significantly associated with planned CD (n = 1,565 infants). Breastfeeding mediated the association between MOD and wheeze but not food allergy. Other factors not associated with early-life microbial transfer, but relating to the development of the outcomes, might contribute to the association between MOD and wheeze/food allergy.

Research paper thumbnail of Concentrations of immune marker in newborn dried blood spots and early childhood development: Results from the Upstate KIDS Study

Paediatric and perinatal epidemiology, Jul 1, 2018

Evidence shows cytokine dysregulation in children with developmental disabilities. The associatio... more Evidence shows cytokine dysregulation in children with developmental disabilities. The association between immune activity during the perinatal period and child development is less clear. We examined the relationship between newborn concentrations of immune markers and child development. Within Upstate KIDS, a population-based birth cohort (2008-2010, upstate New York), we assayed immune markers, which are postulated to have neuro-modulatory effects, in newborn dried blood spots (NDBS, n = 3038). Mothers completed the Ages & Stages Questionnaire© (ASQ) for their children repeatedly through age 36 months. At 30 and 36 months, mothers also reported whether their children received any developmental services. We used generalised linear mixed models adjusted for maternal and child characteristics to test associations. Sixteen immune markers were associated with failing ASQ in unadjusted models. After full adjustment (for gestational age, mode of delivery, parity, pregnancy smoking, etc.)...

Research paper thumbnail of Coordination between Two Branches of the Unfolded Protein Response Determines Apoptotic Cell Fate

Molecular cell, Jan 16, 2018

The kinases PERK and IRE1 alleviate endoplasmic reticulum (ER) stress by orchestrating the unfold... more The kinases PERK and IRE1 alleviate endoplasmic reticulum (ER) stress by orchestrating the unfolded protein response (UPR). If stress mitigation fails, PERK promotes cell death by activating pro-apoptotic genes, including death receptor 5 (DR5). Conversely, IRE1-which harbors both kinase and endoribonuclease (RNase) modules-blocks apoptosis through regulated IRE1-dependent decay (RIDD) of DR5 mRNA. Under irresolvable ER stress, PERK activity persists, whereas IRE1 paradoxically attenuates, by mechanisms that remain obscure. Here, we report that PERK governs IRE1's attenuation through a phosphatase known as RPAP2 (RNA polymerase II-associated protein 2). RPAP2 reverses IRE1 phosphorylation, oligomerization, and RNase activation. This inhibits IRE1-mediated adaptive events, including activation of the cytoprotective transcription factor XBP1s, and ER-associated degradation of unfolded proteins. Furthermore, RIDD termination by RPAP2 unleashes DR5-mediated caspase activation and dr...

Research paper thumbnail of Confirming a critical role for death receptor 5 and caspase-8 in apoptosis induction by endoplasmic reticulum stress

Cell death and differentiation, Jan 10, 2018

Several studies implicate specific death receptors (DRs) and caspase-8 in mediating apoptosis in ... more Several studies implicate specific death receptors (DRs) and caspase-8 in mediating apoptosis in response to endoplasmic reticulum (ER) stress; however, a recent paper challenges this conclusion. Here we validate the importance of DR5 and caspase-8 as critical signal conduits for apoptosis activation upon ER stress.

Research paper thumbnail of From Infections to Anthropogenic Inflicted Pathologies: Involvement of Immune Balance

Journal of toxicology and environmental health. Part B, Critical reviews, Jan 18, 2017

A temporal trend can be seen in recent human history where the dominant causes of death have shif... more A temporal trend can be seen in recent human history where the dominant causes of death have shifted from infectious to chronic diseases in industrialized societies. Human influences in the current "Anthropocene" epoch are exponentially impacting the environment and consequentially health. Changing ecological niches are suggested to have created health transitions expressed as modifications of immune balance from infections inflicting pathologies in the Holocene epoch (12,000 years ago) to human behaviors inflicting pathologies beginning in the Anthropocene epoch (300 years ago). A review of human immune health and adaptations responding to environmental (biological, chemical, physical, and psychological) stresses, which are influenced by social conditions, emphasize the involvement of fluctuations in immune cell subsets affecting influential gene-environment interactions. The literature from a variety of fields (anthropological, immunological, and environmental) is incorp...

Research paper thumbnail of Determinants of neonatal brain-derived neurotrophic factor and association with child development

Development and psychopathology, Oct 2, 2017

Using a population-based birth cohort in upstate New York (2008-2010), we examined the determinan... more Using a population-based birth cohort in upstate New York (2008-2010), we examined the determinants of brain-derived neurotrophic factor (BDNF) measured in newborn dried blood spots (n = 2,637). We also examined the association between neonatal BDNF and children's development. The cohort was initially designed to examine the influence of infertility treatment on child development but found no impact. Mothers rated children's development in five domains repeatedly through age 3 years. Socioeconomic and maternal lifestyle determinants of BDNF were examined using multivariable linear regression models. Generalized linear mixed models estimated odds ratios for neonatal BDNF in relation to failing a developmental domain. Smoking and drinking in pregnancy, nulliparity, non-White ethnicity/race, and prepregnancy obesity were associated with lower neonatal BDNF. Neonatal BDNF was not associated with failure for developmental domains; however, there was an interaction between BDNF an...

Research paper thumbnail of Maternal Smoking and Newborn Cytokine and Immunoglobulin Levels

Nicotine & tobacco research : official journal of the Society for Research on Nicotine and Tobacco, Jan 23, 2016

Prenatal smoking exposure may lead to permanent changes in neonatal inflammation and immune respo... more Prenatal smoking exposure may lead to permanent changes in neonatal inflammation and immune response that have lifelong implications, including increased risks for atopy and respiratory disorders. The effect of maternal smoking on neonatal biomarkers of inflammation and immune response was assessed among 3459 singletons and twins in the Upstate KIDS Study. The following inflammatory biomarkers were measured using newborn dried blood spots (DBSs): interleukin (IL)-1α, IL-1 receptor antagonist, IL-6, IL-8, C-reactive protein, and tumor necrosis factor alpha. Immunoglobulins (IgE, IgA, IgM, and IgG subclasses) were also assessed. We used generalized estimating equations to calculate mean differences (β) in biomarker levels by timing of pregnancy smoking, cigarette load, and secondhand smoke exposure after adjusting for sociodemographic and lifestyle factors including maternal body mass index. Of the 344 (12%) women reporting smoking during pregnancy, about 40% continued throughout preg...

Research paper thumbnail of FORUM Environmental Stress Mediates Changes in Neuroimmunological Interactions

Combinations of environmental stress coordinately increase toxicological assaults on health, depe... more Combinations of environmental stress coordinately increase toxicological assaults on health, dependent on the genetics of the exposed organism. Multiple gene variances between individuals influence the risks associated with environmental exposures, and environmental stress presents in multiple forms including chemical, physical, and psychological stresses. Combined chemical, physical, and psychological stresses are suggested as exacerbating the initiation and/or duration of illnesses, and many of the detrimental outcomes on health are posited to relate to changes in neuroendocrine immune circuitry. However, most human epidemiological or experimental animal studies have not considered the combination of chemical, physical, and psychological stress on health status. Current consideration is being given to "real world" exposures for assessment of health risk, but this mainly relates to evaluation of chemical mixtures. In addition to concomitant chemical exposures having agonistic and/or antagonistic interactions, the physical and psychological status of the individual can influence exposure outcomes. An individual's psychosocial environment is likely to be important in epidemiological investigations. Neuroimmunology is a burgeoning discipline, and neurotoxicology and immunotoxicology studies should consider the bidirectional regulatory mechanisms between these organ systems and the potential long-term influences of psychological stress. This minireview discusses some intriguing data from animal and human studies, which address the regulatory pathways between the neural, endocrine, and immune systems, with emphasis on psychological stress.

Research paper thumbnail of Aberrant Immune Responses in a Mouse with Behavioral Disorders

PLoS ONE, 2011

BTBR T+tf/J (BTBR) mice have recently been reported to have behaviors that resemble those of auti... more BTBR T+tf/J (BTBR) mice have recently been reported to have behaviors that resemble those of autistic individuals, in that this strain has impairments in social interactions and a restricted repetitive and stereotyped pattern of behaviors. Since immune responses, including autoimmune responses, are known to affect behavior, and individuals with autism have aberrant immune activities, we evaluated the immune system of BTBR mice, and compared their immunity and degree of neuroinflammation with that of C57BL/6 (B6) mice, a highly social control strain, and with F1 offspring. Mice were assessed at postnatal day (pnd) 21 and after behavioral analysis at pnd70. BTBR mice had significantly higher amounts of serum IgG and IgE, of IgG anti-brain antibodies (Abs), and of IgG and IgE deposited in the brain, elevated expression of cytokines, especially IL-33 IL-18, and IL-1b in the brain, and an increased proportion of MHC class II-expressing microglia compared to B6 mice. The F1 mice had intermediate levels of Abs and cytokines as well as social activity. The high Ab levels of BTBR mice are in agreement with their increased numbers of CD40 hi /I-A hi B cells and IgG-secreting B cells. Upon immunization with KLH, the BTBR mice produced 2-3 times more anti-KLH Abs than B6 mice. In contrast to humoral immunity, BTBR mice are significantly more susceptible to listeriosis than B6 or BALB/c mice. The Th2-like immune profile of the BTBR mice and their constitutive neuroinflammation suggests that an autoimmune profile is implicated in their aberrant behaviors, as has been suggested for some humans with autism.

Research paper thumbnail of Cell death. Opposing unfolded-protein-response signals converge on death receptor 5 to control apoptosis

Science (New York, N.Y.), Jan 4, 2014

Protein folding by the endoplasmic reticulum (ER) is physiologically critical; its disruption cau... more Protein folding by the endoplasmic reticulum (ER) is physiologically critical; its disruption causes ER stress and augments disease. ER stress activates the unfolded protein response (UPR) to restore homeostasis. If stress persists, the UPR induces apoptotic cell death, but the mechanisms remain elusive. Here, we report that unmitigated ER stress promoted apoptosis through cell-autonomous, UPR-controlled activation of death receptor 5 (DR5). ER stressors induced DR5 transcription via the UPR mediator CHOP; however, the UPR sensor IRE1α transiently catalyzed DR5 mRNA decay, which allowed time for adaptation. Persistent ER stress built up intracellular DR5 protein, driving ligand-independent DR5 activation and apoptosis engagement via caspase-8. Thus, DR5 integrates opposing UPR signals to couple ER stress and apoptotic cell fate.

Research paper thumbnail of Interleukin-12 Promotes Enhanced Resistance toInfection of Lead-Exposed Mice

Toxicology and Applied Pharmacology, 1997

The heavy metal lead (Pb) has been shown to downregulate various parameters of cell-mediated immu... more The heavy metal lead (Pb) has been shown to downregulate various parameters of cell-mediated immune (CMI) responses. This inhibition of CMI responses by Pb is exemplified by a higher mortality rate upon infections with sublethal doses of a variety of pathogens. Unlike Pb, which lowers host resistance, interleukin-12 (IL-12) exerts a substantial stimulatory influence on the host response to intracellular bacteria such as Listeria monocytogenes. To explore the influence of IL-12 in mice rendered susceptible to Listerial infection by oral exposure to Pb, we determined bacterial burdens and production of interferon gamma (IFN-␥). As expected, Pb-exposed mice had increased morbidity due to higher Listerial titers as compared to control mice. However, administration of exogenous IL-12 reversed the Pbinduced inhibition of host defense and boosted the resistance of the non-Pb-treated mice. The enhanced CMI responses observed in both IL-12-treated groups were accompanied with elevations of IFN-␥ in the sera and spleens. Significant reduction in the number of viable Listeria in Pb-exposed mice upon IL-12 administration suggests that the processes downstream of IL-12 production were intact in the Pb-exposed mice and that the inhibition by Pb was due to the lack of functional IL-12. Alternatively, the exogenous IL-12 may have overcome a downstream effect by enhancing an secondary pathway. Support for the former hypothesis is based on the observation that Pb induced elevated levels of p40 splenic messenger RNA since increased p40 expression would result from lack of IL-12 formation. Contrary to the IFN-␥ levels, significantly higher levels of IL-6 and corticosterone were observed in the sera and spleens of Pb-exposed mice upon infection, suggesting heightened stress in the absence of IL-12. Overall, the results suggest that an environmental pollutant such as Pb can enhance the stress response, which naturally occurs during an infection, and can further compromise health by lowering host resistance by altering cytokine levels.

Research paper thumbnail of Impact of developmental lead exposure on splenic factors

Toxicology and Applied Pharmacology, 2010

Lead (Pb) is known to alter the functions of numerous organ systems, including the hematopoietic ... more Lead (Pb) is known to alter the functions of numerous organ systems, including the hematopoietic and immune systems. Pb can induce anemia and can lower host resistance to bacterial and viral infections. The anemia is due to Pb's inhibition of hemoglobin synthesis and Pb's induction of membrane changes, leading to early erythrocyte senescence. Pb also increases B-cell activation/ proliferation and skews T-cell help (Th) toward Th2 subset generation. The specific mechanisms for many of the Pb effects are, as yet, not completely understood. Therefore, we performed gene expression analysis, via microarray, on RNA from the spleens of developmentally Pb-exposed mice, in order to gain further insight into these Pb effects. Splenic RNA microarray analysis indicated strong up-regulation of genes coding for proteolytic enzymes, lipases, amylase, and RNaseA. The data also showed that Pb affected the expression of many genes associated with innate immunity. Analysis of the microarray results via GeneSifter software indicated that Pb increased apoptosis, B-cell differentiation, and Th2 development. Direct up-regulation by Pb of expression of the gene encoding the heme-regulated inhibitor (HRI) suggested that Pb can decrease erythropoiesis by blocking globin mRNA translation. Pb's high elevation of digestive/ catabolizing enzymes could generate immunogenic self peptides. With Pb's potential to induce new self-peptides and to enhance the expression of caspases, cytokines, and other immunomodulators, further evaluation of Pb's involvement in autoimmune phenomena, especially Th2-mediated autoantibody production, and alteration of organ system activities is warranted.

Research paper thumbnail of Central/peripheral nervous system and immune responses

Toxicology, 2000

Maintenance of health is dependent on numerous regulatory interactions between organ systems. Thi... more Maintenance of health is dependent on numerous regulatory interactions between organ systems. This review discusses interorgan communication between the nervous, endocrine, and immune systems and environmental and genetic influences on this neuroendocrine immune circuitry. Stresses of multiple types, including psychological and exposure to chemicals and infectious agents, may combine to enhance neuroimmunotoxicology. Altered nervous system functions can alter immunity which could result in exacerbation of infections, cancers or other immune-associated problems. Inversely, abberant immune system activities could lead to pathologies associated with altered nervous activities, such as Alzheimer's disease, chronic fatigue, or multiple sclerosis. The nervous, endocrine and immune circuitry is multi-directional, and a chemical, physical or emotional stress could upset the homeostasis.

Research paper thumbnail of Shrinking the Biologic World--Nanobiotechnologies for Toxicology

Toxicological Sciences, 2003

Although toxicologic effects need to be considered at the organismal level, the adverse events or... more Although toxicologic effects need to be considered at the organismal level, the adverse events originate from interactions and alterations at the molecular level. Cellular structures and functions can be disrupted by modifications of the nanometer structure of critical molecules; therefore, devices used to assess biologic and toxicologic processes at the nanoscale will allow important new research pursuits. In order to properly assess alterations at these dimensions, nanofabricated tools are needed to detect, separate, analyze, and manipulate cells or biologic molecules of interest. The emergence of laser tweezers, surface plasmon resonance (SPR), laser capture microdissection (LCM), atomic force microscopy (AFM), and multi-photon microscopes have allowed for these assessments. Micro-and nanobiotechnologies will further advance biologic, clinical, and toxicologic endeavors with the aid of miniaturized, more sensitive devices. Miniaturized table-top laboratory equipment incorporating additional innovative technologies can lead to new advances, including micro total analysis systems (TAS) or "lab-on-a-chip" and "sentinel sensor" devices. This review will highlight several devices, which have been made possible by techniques originating in the microelectronics industry. These devices can be used for toxicologic assessment of cellular structures and functions, such as cellular adhesion, signal transduction, motility, deformability, metabolism, and secretion.

Research paper thumbnail of Environmental Stress Mediates Changes in Neuroimmunological Interactions

Toxicological Sciences, 2002

Combinations of environmental stress coordinately increase toxicological assaults on health, depe... more Combinations of environmental stress coordinately increase toxicological assaults on health, dependent on the genetics of the exposed organism. Multiple gene variances between individuals influence the risks associated with environmental exposures, and environmental stress presents in multiple forms including chemical, physical, and psychological stresses. Combined chemical, physical, and psychological stresses are suggested as exacerbating the initiation and/or duration of illnesses, and many of the detrimental outcomes on health are posited to relate to changes in neuroendocrine immune circuitry. However, most human epidemiological or experimental animal studies have not considered the combination of chemical, physical, and psychological stress on health status. Current consideration is being given to "real world" exposures for assessment of health risk, but this mainly relates to evaluation of chemical mixtures. In addition to concomitant chemical exposures having agonistic and/or antagonistic interactions, the physical and psychological status of the individual can influence exposure outcomes. An individual's psychosocial environment is likely to be important in epidemiological investigations. Neuroimmunology is a burgeoning discipline, and neurotoxicology and immunotoxicology studies should consider the bidirectional regulatory mechanisms between these organ systems and the potential long-term influences of psychological stress. This minireview discusses some intriguing data from animal and human studies, which address the regulatory pathways between the neural, endocrine, and immune systems, with emphasis on psychological stress.

Research paper thumbnail of Posttranscriptional Inhibition of Interferon-Gamma Production by Lead

Toxicological Sciences, 2006

Research paper thumbnail of Death-receptor activation halts clathrin-dependent endocytosis

Proceedings of the National Academy of Sciences, 2006

Endocytosis is crucial for various aspects of cell homeostasis. Here, we show that proapoptotic d... more Endocytosis is crucial for various aspects of cell homeostasis. Here, we show that proapoptotic death receptors (DRs) trigger selective destruction of the clathrin-dependent endocytosis machinery. DR stimulation induced rapid, caspase-mediated cleavage of key clathrin-pathway components, halting cellular uptake of the classic cargo protein transferrin. DR-proximal initiator caspases cleaved the clathrin adaptor subunit AP2α between functionally distinct domains, whereas effector caspases processed clathrin’s heavy chain. DR5 underwent ligand-induced, clathrin-mediated endocytosis, suggesting that internalization of DR signaling complexes facilitates clathrin-pathway targeting by caspases. An endocytosis-blocking, temperature-sensitive dynamin-1 mutant attenuated DR internalization, enhanced caspase stimulation downstream of DRs, and increased apoptosis. Thus, DR-triggered caspase activity disrupts clathrin-dependent endocytosis, leading to amplification of programmed cell death.

Research paper thumbnail of Mercury Impairment of Mouse Thymocyte Survival in Vitro: Involvement of Cellular Thiols

Journal of Toxicology and Environmental Health, Part A, 2005

Heavy metals are well known to be able to induce immunotoxicity, but comparative metal studies re... more Heavy metals are well known to be able to induce immunotoxicity, but comparative metal studies related to apoptosis have not been conducted. In the present study, the effects of arsenic, cadmium, gold, lead, manganese, and mercury on thymocytes from BALB/c mice were analyzed. Thymic cells were cultured for 3-24 h in vitro in the absence or presence of metal, and markers of apoptosis or cell death, including annexin V binding, DNA loss/oligonucleosomal fragmentation, 7-amino-actinomycin D uptake (loss of impermeance), changes of the mitochondrial membrane potential (JC-1 fluorescence), and Western analysis of cellular thiols, were assayed. Mercury (Hg) was the only metal shown to be consistently toxic with the dose and times utilized. Cadmium (Cd) was the only other metal tested that also produced some significant level of DNA loss; however, the induction of apoptosis by Cd was not as consistent as that observed with Hg. When Hg was added with 2-mercaptoethanol (2-ME), Hg produced greater toxicity. Endogenous DNA synthesis by thymocytes was immediately inhibited by Hg and Hg + 2-ME. The Hg + 2-ME-induced apoptosis appeared to be associated with altered levels of cellular thiols, in that glutathione (GSH) depletion was significant in comparison to the non-metal control and Hg alone. The increased Hg-induced toxicity in the presence of 2-ME likely was due to the ability of 2-ME to enhance (10- to 20-fold) the cellular uptake of Hg. Western analysis with biotin maleimide demonstrated that Hg + 2-ME and to a lesser extent the positive control dexamethasone eliminated many reactive thiols; the major thiol-reactive protein still reactive with the maleimide probe had an approximate Molecular Mass of 45 kD. Surprisingly, Hg alone enhanced the expression of this thiol-expressing protein, which by Mass Spectrometry (MS)/MS analysis was shown to be beta-actin. Hg also produced the appearance of yet to be identified new proteins. Based on the results with Hg + 2-ME, it is suggested that numerous protein thiols participate in maintenance of cell survival and their loss is associated with apoptosis. The increased expression of new thiol-reactive proteins or thiol-reactive proteins with altered electrophoretic profiles needs to be further investigated. However, the enhanced toxicity attributed to Hg + 2-ME suggests that increased intracellular oxidative stress, observed as increased depletion of GSH, is responsible for the accelerated cell death.

Research paper thumbnail of Suppression of host resistance to Listeria monocytogenes by acute cold/restraint stress: lack of direct IL-6 involvement

Journal of Neuroimmunology, 2002

We conducted kinetic studies to evaluate the effects of acute cold/restraint stress (ACRS) on bot... more We conducted kinetic studies to evaluate the effects of acute cold/restraint stress (ACRS) on both primary and secondary host resistance to Listeria monocytogenes (LM). The involvement of IL-6 also was investigated using IL-6 knockout (KO) mice on the BALB/c background. ACRS dramatically increased the serum corticosterone levels, indicating that ACRS activated the hypothalamic-pituitary-adrenal (HPA) axis. ACRS significantly inhibited host resistance to LM during a primary but not a secondary LM infection. During the primary infection, ACRS caused a significant delay in clearance of LM, loss of body weight, reduced food/water intake, and elevated levels of pro-inflammatory cytokines (IL-6, IL-1beta, and TNFalpha) and IFNgamma. ACRS IL-6 KO mice showed higher LM burdens than did IL-6 KO controls, suggesting that IL-6 is not required for the ACRS-impairment of host resistance. Elevated levels of IL-1beta and TNFalpha may compensate for the absence of IL-6 and maintain the ACRS-induced impairment, in that the serum and splenic IL-1beta and TNFalpha levels were significantly higher in infected ACRS IL-6 KO mice, but not in control IL-6 KO mice, as compared to respective wild type controls. ACRS appears to inhibit IL-6 independent mechanisms associated with innate immunity and/or the development of adaptive immunity, but these reactions are unable to modulate the more efficient secondary immune responses.

Research paper thumbnail of β1-Adrenergic Receptors on Immune Cells Impair Innate Defenses against Listeria

The Journal of Immunology, 2007

Cold restraint (CR) for 1 h elicits a psychological and physiological stress that inhibits host d... more Cold restraint (CR) for 1 h elicits a psychological and physiological stress that inhibits host defenses against Listeria monocytogenes (LM). Previous analyses indicated that this inhibition is not due to depletion of B or T cells but is instead dependent on signaling through ␤-adrenoceptors (␤ARs). We now show that impaired host resistance by CR cannot be accounted for by a decrease in LM-specific (listeriolysin O 91-99 tetramer ؉) effector CD8 ؉ T cells; this result is consistent with previous observations that CRinduced effects are mainly limited to early anti-LM responses. ␤2-Adrenoceptor (␤2AR) ؊/؊ FVB/NJ and wild-type FVB/NJ mice had equivalent anti-LM defenses, whereas ␤1-adrenoceptor (␤1AR) ؊/؊ FVB/NJ mice had lower levels of LM even when subjected to CR treatment. Additionally, host-resistance competency of ␤1AR ؊/؊ mice could be transferred to irradiated wild-type mice reconstituted with ␤1AR ؊/؊ bone marrow progenitors and spleen cells, indicating that ␤1AR signaling on immune cells reduces anti-LM responses. ␤1AR ؊/؊ mice had improved cellular (delayed-type hypersensitivity) responses while ␤2AR ؊/؊ mice had improved humoral responses (IgG1, IgG2, and IgM), a result that further explains the strain differences in LM defenses. CRinduced expression of ␤1AR and ␤2AR mRNA was assessed by real-time PCR. CR treatment significantly increased ␤AR mRNAs in Ficoll-purified and F4/80 ؉-enhanced liver but not splenic homogenates, demonstrating an organ-specific effect of stress that alters host defenses. Finally, CR treatment induced early increases in perforin expression that may enhance immune cell apoptosis and interfere with LM clearance. In conclusion, ␤1AR signaling has immunomodulatory effects on early cell-mediated immune responses; a lack of ␤1AR signaling improves antilisterial defenses and cell-mediated immunity, in general.

Research paper thumbnail of Wheeze and Food Allergies in Children Born via Cesarean Delivery

American Journal of Epidemiology, 2018

We examined whether cesarean delivery (CD) increased the risk of wheeze or food allergy in early ... more We examined whether cesarean delivery (CD) increased the risk of wheeze or food allergy in early childhood compared with vaginal delivery and whether these associations were mediated by breastfeeding. The study population was the Upstate KIDS cohort (2008-2010) of mothers and infants from the State of New York (excluding New York City). Infant's wheeze was reported by questionnaire every 4-6 months until 3 years of age, as were food allergies beginning at 8 months. Modified Poisson regression was used to compare risks of the outcomes according to mode of delivery (MOD). Potential confounders were identified a priori using directed acyclic graphs. Emergency CD (n = 1,356) was associated with elevated risk of wheeze, adjusting for pregnancy complications, maternal atopy, gestational age, birth weight, and smoking during pregnancy (risk ratio = 2.47, 95% confidence interval: 1.31, 4.66), and an increased risk of food allergy, adjusting for maternal atopy, prepregnancy body mass index, smoking during pregnancy, and parity (risk ratio = 3.02, 95% confidence interval: 1.26, 7.25). Neither outcome was significantly associated with planned CD (n = 1,565 infants). Breastfeeding mediated the association between MOD and wheeze but not food allergy. Other factors not associated with early-life microbial transfer, but relating to the development of the outcomes, might contribute to the association between MOD and wheeze/food allergy.

Research paper thumbnail of Concentrations of immune marker in newborn dried blood spots and early childhood development: Results from the Upstate KIDS Study

Paediatric and perinatal epidemiology, Jul 1, 2018

Evidence shows cytokine dysregulation in children with developmental disabilities. The associatio... more Evidence shows cytokine dysregulation in children with developmental disabilities. The association between immune activity during the perinatal period and child development is less clear. We examined the relationship between newborn concentrations of immune markers and child development. Within Upstate KIDS, a population-based birth cohort (2008-2010, upstate New York), we assayed immune markers, which are postulated to have neuro-modulatory effects, in newborn dried blood spots (NDBS, n = 3038). Mothers completed the Ages & Stages Questionnaire© (ASQ) for their children repeatedly through age 36 months. At 30 and 36 months, mothers also reported whether their children received any developmental services. We used generalised linear mixed models adjusted for maternal and child characteristics to test associations. Sixteen immune markers were associated with failing ASQ in unadjusted models. After full adjustment (for gestational age, mode of delivery, parity, pregnancy smoking, etc.)...

Research paper thumbnail of Coordination between Two Branches of the Unfolded Protein Response Determines Apoptotic Cell Fate

Molecular cell, Jan 16, 2018

The kinases PERK and IRE1 alleviate endoplasmic reticulum (ER) stress by orchestrating the unfold... more The kinases PERK and IRE1 alleviate endoplasmic reticulum (ER) stress by orchestrating the unfolded protein response (UPR). If stress mitigation fails, PERK promotes cell death by activating pro-apoptotic genes, including death receptor 5 (DR5). Conversely, IRE1-which harbors both kinase and endoribonuclease (RNase) modules-blocks apoptosis through regulated IRE1-dependent decay (RIDD) of DR5 mRNA. Under irresolvable ER stress, PERK activity persists, whereas IRE1 paradoxically attenuates, by mechanisms that remain obscure. Here, we report that PERK governs IRE1's attenuation through a phosphatase known as RPAP2 (RNA polymerase II-associated protein 2). RPAP2 reverses IRE1 phosphorylation, oligomerization, and RNase activation. This inhibits IRE1-mediated adaptive events, including activation of the cytoprotective transcription factor XBP1s, and ER-associated degradation of unfolded proteins. Furthermore, RIDD termination by RPAP2 unleashes DR5-mediated caspase activation and dr...

Research paper thumbnail of Confirming a critical role for death receptor 5 and caspase-8 in apoptosis induction by endoplasmic reticulum stress

Cell death and differentiation, Jan 10, 2018

Several studies implicate specific death receptors (DRs) and caspase-8 in mediating apoptosis in ... more Several studies implicate specific death receptors (DRs) and caspase-8 in mediating apoptosis in response to endoplasmic reticulum (ER) stress; however, a recent paper challenges this conclusion. Here we validate the importance of DR5 and caspase-8 as critical signal conduits for apoptosis activation upon ER stress.

Research paper thumbnail of From Infections to Anthropogenic Inflicted Pathologies: Involvement of Immune Balance

Journal of toxicology and environmental health. Part B, Critical reviews, Jan 18, 2017

A temporal trend can be seen in recent human history where the dominant causes of death have shif... more A temporal trend can be seen in recent human history where the dominant causes of death have shifted from infectious to chronic diseases in industrialized societies. Human influences in the current "Anthropocene" epoch are exponentially impacting the environment and consequentially health. Changing ecological niches are suggested to have created health transitions expressed as modifications of immune balance from infections inflicting pathologies in the Holocene epoch (12,000 years ago) to human behaviors inflicting pathologies beginning in the Anthropocene epoch (300 years ago). A review of human immune health and adaptations responding to environmental (biological, chemical, physical, and psychological) stresses, which are influenced by social conditions, emphasize the involvement of fluctuations in immune cell subsets affecting influential gene-environment interactions. The literature from a variety of fields (anthropological, immunological, and environmental) is incorp...

Research paper thumbnail of Determinants of neonatal brain-derived neurotrophic factor and association with child development

Development and psychopathology, Oct 2, 2017

Using a population-based birth cohort in upstate New York (2008-2010), we examined the determinan... more Using a population-based birth cohort in upstate New York (2008-2010), we examined the determinants of brain-derived neurotrophic factor (BDNF) measured in newborn dried blood spots (n = 2,637). We also examined the association between neonatal BDNF and children's development. The cohort was initially designed to examine the influence of infertility treatment on child development but found no impact. Mothers rated children's development in five domains repeatedly through age 3 years. Socioeconomic and maternal lifestyle determinants of BDNF were examined using multivariable linear regression models. Generalized linear mixed models estimated odds ratios for neonatal BDNF in relation to failing a developmental domain. Smoking and drinking in pregnancy, nulliparity, non-White ethnicity/race, and prepregnancy obesity were associated with lower neonatal BDNF. Neonatal BDNF was not associated with failure for developmental domains; however, there was an interaction between BDNF an...

Research paper thumbnail of Maternal Smoking and Newborn Cytokine and Immunoglobulin Levels

Nicotine & tobacco research : official journal of the Society for Research on Nicotine and Tobacco, Jan 23, 2016

Prenatal smoking exposure may lead to permanent changes in neonatal inflammation and immune respo... more Prenatal smoking exposure may lead to permanent changes in neonatal inflammation and immune response that have lifelong implications, including increased risks for atopy and respiratory disorders. The effect of maternal smoking on neonatal biomarkers of inflammation and immune response was assessed among 3459 singletons and twins in the Upstate KIDS Study. The following inflammatory biomarkers were measured using newborn dried blood spots (DBSs): interleukin (IL)-1α, IL-1 receptor antagonist, IL-6, IL-8, C-reactive protein, and tumor necrosis factor alpha. Immunoglobulins (IgE, IgA, IgM, and IgG subclasses) were also assessed. We used generalized estimating equations to calculate mean differences (β) in biomarker levels by timing of pregnancy smoking, cigarette load, and secondhand smoke exposure after adjusting for sociodemographic and lifestyle factors including maternal body mass index. Of the 344 (12%) women reporting smoking during pregnancy, about 40% continued throughout preg...

Research paper thumbnail of FORUM Environmental Stress Mediates Changes in Neuroimmunological Interactions

Combinations of environmental stress coordinately increase toxicological assaults on health, depe... more Combinations of environmental stress coordinately increase toxicological assaults on health, dependent on the genetics of the exposed organism. Multiple gene variances between individuals influence the risks associated with environmental exposures, and environmental stress presents in multiple forms including chemical, physical, and psychological stresses. Combined chemical, physical, and psychological stresses are suggested as exacerbating the initiation and/or duration of illnesses, and many of the detrimental outcomes on health are posited to relate to changes in neuroendocrine immune circuitry. However, most human epidemiological or experimental animal studies have not considered the combination of chemical, physical, and psychological stress on health status. Current consideration is being given to "real world" exposures for assessment of health risk, but this mainly relates to evaluation of chemical mixtures. In addition to concomitant chemical exposures having agonistic and/or antagonistic interactions, the physical and psychological status of the individual can influence exposure outcomes. An individual's psychosocial environment is likely to be important in epidemiological investigations. Neuroimmunology is a burgeoning discipline, and neurotoxicology and immunotoxicology studies should consider the bidirectional regulatory mechanisms between these organ systems and the potential long-term influences of psychological stress. This minireview discusses some intriguing data from animal and human studies, which address the regulatory pathways between the neural, endocrine, and immune systems, with emphasis on psychological stress.

Research paper thumbnail of Aberrant Immune Responses in a Mouse with Behavioral Disorders

PLoS ONE, 2011

BTBR T+tf/J (BTBR) mice have recently been reported to have behaviors that resemble those of auti... more BTBR T+tf/J (BTBR) mice have recently been reported to have behaviors that resemble those of autistic individuals, in that this strain has impairments in social interactions and a restricted repetitive and stereotyped pattern of behaviors. Since immune responses, including autoimmune responses, are known to affect behavior, and individuals with autism have aberrant immune activities, we evaluated the immune system of BTBR mice, and compared their immunity and degree of neuroinflammation with that of C57BL/6 (B6) mice, a highly social control strain, and with F1 offspring. Mice were assessed at postnatal day (pnd) 21 and after behavioral analysis at pnd70. BTBR mice had significantly higher amounts of serum IgG and IgE, of IgG anti-brain antibodies (Abs), and of IgG and IgE deposited in the brain, elevated expression of cytokines, especially IL-33 IL-18, and IL-1b in the brain, and an increased proportion of MHC class II-expressing microglia compared to B6 mice. The F1 mice had intermediate levels of Abs and cytokines as well as social activity. The high Ab levels of BTBR mice are in agreement with their increased numbers of CD40 hi /I-A hi B cells and IgG-secreting B cells. Upon immunization with KLH, the BTBR mice produced 2-3 times more anti-KLH Abs than B6 mice. In contrast to humoral immunity, BTBR mice are significantly more susceptible to listeriosis than B6 or BALB/c mice. The Th2-like immune profile of the BTBR mice and their constitutive neuroinflammation suggests that an autoimmune profile is implicated in their aberrant behaviors, as has been suggested for some humans with autism.

Research paper thumbnail of Cell death. Opposing unfolded-protein-response signals converge on death receptor 5 to control apoptosis

Science (New York, N.Y.), Jan 4, 2014

Protein folding by the endoplasmic reticulum (ER) is physiologically critical; its disruption cau... more Protein folding by the endoplasmic reticulum (ER) is physiologically critical; its disruption causes ER stress and augments disease. ER stress activates the unfolded protein response (UPR) to restore homeostasis. If stress persists, the UPR induces apoptotic cell death, but the mechanisms remain elusive. Here, we report that unmitigated ER stress promoted apoptosis through cell-autonomous, UPR-controlled activation of death receptor 5 (DR5). ER stressors induced DR5 transcription via the UPR mediator CHOP; however, the UPR sensor IRE1α transiently catalyzed DR5 mRNA decay, which allowed time for adaptation. Persistent ER stress built up intracellular DR5 protein, driving ligand-independent DR5 activation and apoptosis engagement via caspase-8. Thus, DR5 integrates opposing UPR signals to couple ER stress and apoptotic cell fate.

Research paper thumbnail of Interleukin-12 Promotes Enhanced Resistance toInfection of Lead-Exposed Mice

Toxicology and Applied Pharmacology, 1997

The heavy metal lead (Pb) has been shown to downregulate various parameters of cell-mediated immu... more The heavy metal lead (Pb) has been shown to downregulate various parameters of cell-mediated immune (CMI) responses. This inhibition of CMI responses by Pb is exemplified by a higher mortality rate upon infections with sublethal doses of a variety of pathogens. Unlike Pb, which lowers host resistance, interleukin-12 (IL-12) exerts a substantial stimulatory influence on the host response to intracellular bacteria such as Listeria monocytogenes. To explore the influence of IL-12 in mice rendered susceptible to Listerial infection by oral exposure to Pb, we determined bacterial burdens and production of interferon gamma (IFN-␥). As expected, Pb-exposed mice had increased morbidity due to higher Listerial titers as compared to control mice. However, administration of exogenous IL-12 reversed the Pbinduced inhibition of host defense and boosted the resistance of the non-Pb-treated mice. The enhanced CMI responses observed in both IL-12-treated groups were accompanied with elevations of IFN-␥ in the sera and spleens. Significant reduction in the number of viable Listeria in Pb-exposed mice upon IL-12 administration suggests that the processes downstream of IL-12 production were intact in the Pb-exposed mice and that the inhibition by Pb was due to the lack of functional IL-12. Alternatively, the exogenous IL-12 may have overcome a downstream effect by enhancing an secondary pathway. Support for the former hypothesis is based on the observation that Pb induced elevated levels of p40 splenic messenger RNA since increased p40 expression would result from lack of IL-12 formation. Contrary to the IFN-␥ levels, significantly higher levels of IL-6 and corticosterone were observed in the sera and spleens of Pb-exposed mice upon infection, suggesting heightened stress in the absence of IL-12. Overall, the results suggest that an environmental pollutant such as Pb can enhance the stress response, which naturally occurs during an infection, and can further compromise health by lowering host resistance by altering cytokine levels.

Research paper thumbnail of Impact of developmental lead exposure on splenic factors

Toxicology and Applied Pharmacology, 2010

Lead (Pb) is known to alter the functions of numerous organ systems, including the hematopoietic ... more Lead (Pb) is known to alter the functions of numerous organ systems, including the hematopoietic and immune systems. Pb can induce anemia and can lower host resistance to bacterial and viral infections. The anemia is due to Pb's inhibition of hemoglobin synthesis and Pb's induction of membrane changes, leading to early erythrocyte senescence. Pb also increases B-cell activation/ proliferation and skews T-cell help (Th) toward Th2 subset generation. The specific mechanisms for many of the Pb effects are, as yet, not completely understood. Therefore, we performed gene expression analysis, via microarray, on RNA from the spleens of developmentally Pb-exposed mice, in order to gain further insight into these Pb effects. Splenic RNA microarray analysis indicated strong up-regulation of genes coding for proteolytic enzymes, lipases, amylase, and RNaseA. The data also showed that Pb affected the expression of many genes associated with innate immunity. Analysis of the microarray results via GeneSifter software indicated that Pb increased apoptosis, B-cell differentiation, and Th2 development. Direct up-regulation by Pb of expression of the gene encoding the heme-regulated inhibitor (HRI) suggested that Pb can decrease erythropoiesis by blocking globin mRNA translation. Pb's high elevation of digestive/ catabolizing enzymes could generate immunogenic self peptides. With Pb's potential to induce new self-peptides and to enhance the expression of caspases, cytokines, and other immunomodulators, further evaluation of Pb's involvement in autoimmune phenomena, especially Th2-mediated autoantibody production, and alteration of organ system activities is warranted.

Research paper thumbnail of Central/peripheral nervous system and immune responses

Toxicology, 2000

Maintenance of health is dependent on numerous regulatory interactions between organ systems. Thi... more Maintenance of health is dependent on numerous regulatory interactions between organ systems. This review discusses interorgan communication between the nervous, endocrine, and immune systems and environmental and genetic influences on this neuroendocrine immune circuitry. Stresses of multiple types, including psychological and exposure to chemicals and infectious agents, may combine to enhance neuroimmunotoxicology. Altered nervous system functions can alter immunity which could result in exacerbation of infections, cancers or other immune-associated problems. Inversely, abberant immune system activities could lead to pathologies associated with altered nervous activities, such as Alzheimer's disease, chronic fatigue, or multiple sclerosis. The nervous, endocrine and immune circuitry is multi-directional, and a chemical, physical or emotional stress could upset the homeostasis.

Research paper thumbnail of Shrinking the Biologic World--Nanobiotechnologies for Toxicology

Toxicological Sciences, 2003

Although toxicologic effects need to be considered at the organismal level, the adverse events or... more Although toxicologic effects need to be considered at the organismal level, the adverse events originate from interactions and alterations at the molecular level. Cellular structures and functions can be disrupted by modifications of the nanometer structure of critical molecules; therefore, devices used to assess biologic and toxicologic processes at the nanoscale will allow important new research pursuits. In order to properly assess alterations at these dimensions, nanofabricated tools are needed to detect, separate, analyze, and manipulate cells or biologic molecules of interest. The emergence of laser tweezers, surface plasmon resonance (SPR), laser capture microdissection (LCM), atomic force microscopy (AFM), and multi-photon microscopes have allowed for these assessments. Micro-and nanobiotechnologies will further advance biologic, clinical, and toxicologic endeavors with the aid of miniaturized, more sensitive devices. Miniaturized table-top laboratory equipment incorporating additional innovative technologies can lead to new advances, including micro total analysis systems (TAS) or "lab-on-a-chip" and "sentinel sensor" devices. This review will highlight several devices, which have been made possible by techniques originating in the microelectronics industry. These devices can be used for toxicologic assessment of cellular structures and functions, such as cellular adhesion, signal transduction, motility, deformability, metabolism, and secretion.

Research paper thumbnail of Environmental Stress Mediates Changes in Neuroimmunological Interactions

Toxicological Sciences, 2002

Combinations of environmental stress coordinately increase toxicological assaults on health, depe... more Combinations of environmental stress coordinately increase toxicological assaults on health, dependent on the genetics of the exposed organism. Multiple gene variances between individuals influence the risks associated with environmental exposures, and environmental stress presents in multiple forms including chemical, physical, and psychological stresses. Combined chemical, physical, and psychological stresses are suggested as exacerbating the initiation and/or duration of illnesses, and many of the detrimental outcomes on health are posited to relate to changes in neuroendocrine immune circuitry. However, most human epidemiological or experimental animal studies have not considered the combination of chemical, physical, and psychological stress on health status. Current consideration is being given to "real world" exposures for assessment of health risk, but this mainly relates to evaluation of chemical mixtures. In addition to concomitant chemical exposures having agonistic and/or antagonistic interactions, the physical and psychological status of the individual can influence exposure outcomes. An individual's psychosocial environment is likely to be important in epidemiological investigations. Neuroimmunology is a burgeoning discipline, and neurotoxicology and immunotoxicology studies should consider the bidirectional regulatory mechanisms between these organ systems and the potential long-term influences of psychological stress. This minireview discusses some intriguing data from animal and human studies, which address the regulatory pathways between the neural, endocrine, and immune systems, with emphasis on psychological stress.

Research paper thumbnail of Posttranscriptional Inhibition of Interferon-Gamma Production by Lead

Toxicological Sciences, 2006

Research paper thumbnail of Death-receptor activation halts clathrin-dependent endocytosis

Proceedings of the National Academy of Sciences, 2006

Endocytosis is crucial for various aspects of cell homeostasis. Here, we show that proapoptotic d... more Endocytosis is crucial for various aspects of cell homeostasis. Here, we show that proapoptotic death receptors (DRs) trigger selective destruction of the clathrin-dependent endocytosis machinery. DR stimulation induced rapid, caspase-mediated cleavage of key clathrin-pathway components, halting cellular uptake of the classic cargo protein transferrin. DR-proximal initiator caspases cleaved the clathrin adaptor subunit AP2α between functionally distinct domains, whereas effector caspases processed clathrin’s heavy chain. DR5 underwent ligand-induced, clathrin-mediated endocytosis, suggesting that internalization of DR signaling complexes facilitates clathrin-pathway targeting by caspases. An endocytosis-blocking, temperature-sensitive dynamin-1 mutant attenuated DR internalization, enhanced caspase stimulation downstream of DRs, and increased apoptosis. Thus, DR-triggered caspase activity disrupts clathrin-dependent endocytosis, leading to amplification of programmed cell death.

Research paper thumbnail of Mercury Impairment of Mouse Thymocyte Survival in Vitro: Involvement of Cellular Thiols

Journal of Toxicology and Environmental Health, Part A, 2005

Heavy metals are well known to be able to induce immunotoxicity, but comparative metal studies re... more Heavy metals are well known to be able to induce immunotoxicity, but comparative metal studies related to apoptosis have not been conducted. In the present study, the effects of arsenic, cadmium, gold, lead, manganese, and mercury on thymocytes from BALB/c mice were analyzed. Thymic cells were cultured for 3-24 h in vitro in the absence or presence of metal, and markers of apoptosis or cell death, including annexin V binding, DNA loss/oligonucleosomal fragmentation, 7-amino-actinomycin D uptake (loss of impermeance), changes of the mitochondrial membrane potential (JC-1 fluorescence), and Western analysis of cellular thiols, were assayed. Mercury (Hg) was the only metal shown to be consistently toxic with the dose and times utilized. Cadmium (Cd) was the only other metal tested that also produced some significant level of DNA loss; however, the induction of apoptosis by Cd was not as consistent as that observed with Hg. When Hg was added with 2-mercaptoethanol (2-ME), Hg produced greater toxicity. Endogenous DNA synthesis by thymocytes was immediately inhibited by Hg and Hg + 2-ME. The Hg + 2-ME-induced apoptosis appeared to be associated with altered levels of cellular thiols, in that glutathione (GSH) depletion was significant in comparison to the non-metal control and Hg alone. The increased Hg-induced toxicity in the presence of 2-ME likely was due to the ability of 2-ME to enhance (10- to 20-fold) the cellular uptake of Hg. Western analysis with biotin maleimide demonstrated that Hg + 2-ME and to a lesser extent the positive control dexamethasone eliminated many reactive thiols; the major thiol-reactive protein still reactive with the maleimide probe had an approximate Molecular Mass of 45 kD. Surprisingly, Hg alone enhanced the expression of this thiol-expressing protein, which by Mass Spectrometry (MS)/MS analysis was shown to be beta-actin. Hg also produced the appearance of yet to be identified new proteins. Based on the results with Hg + 2-ME, it is suggested that numerous protein thiols participate in maintenance of cell survival and their loss is associated with apoptosis. The increased expression of new thiol-reactive proteins or thiol-reactive proteins with altered electrophoretic profiles needs to be further investigated. However, the enhanced toxicity attributed to Hg + 2-ME suggests that increased intracellular oxidative stress, observed as increased depletion of GSH, is responsible for the accelerated cell death.

Research paper thumbnail of Suppression of host resistance to Listeria monocytogenes by acute cold/restraint stress: lack of direct IL-6 involvement

Journal of Neuroimmunology, 2002

We conducted kinetic studies to evaluate the effects of acute cold/restraint stress (ACRS) on bot... more We conducted kinetic studies to evaluate the effects of acute cold/restraint stress (ACRS) on both primary and secondary host resistance to Listeria monocytogenes (LM). The involvement of IL-6 also was investigated using IL-6 knockout (KO) mice on the BALB/c background. ACRS dramatically increased the serum corticosterone levels, indicating that ACRS activated the hypothalamic-pituitary-adrenal (HPA) axis. ACRS significantly inhibited host resistance to LM during a primary but not a secondary LM infection. During the primary infection, ACRS caused a significant delay in clearance of LM, loss of body weight, reduced food/water intake, and elevated levels of pro-inflammatory cytokines (IL-6, IL-1beta, and TNFalpha) and IFNgamma. ACRS IL-6 KO mice showed higher LM burdens than did IL-6 KO controls, suggesting that IL-6 is not required for the ACRS-impairment of host resistance. Elevated levels of IL-1beta and TNFalpha may compensate for the absence of IL-6 and maintain the ACRS-induced impairment, in that the serum and splenic IL-1beta and TNFalpha levels were significantly higher in infected ACRS IL-6 KO mice, but not in control IL-6 KO mice, as compared to respective wild type controls. ACRS appears to inhibit IL-6 independent mechanisms associated with innate immunity and/or the development of adaptive immunity, but these reactions are unable to modulate the more efficient secondary immune responses.

Research paper thumbnail of β1-Adrenergic Receptors on Immune Cells Impair Innate Defenses against Listeria

The Journal of Immunology, 2007

Cold restraint (CR) for 1 h elicits a psychological and physiological stress that inhibits host d... more Cold restraint (CR) for 1 h elicits a psychological and physiological stress that inhibits host defenses against Listeria monocytogenes (LM). Previous analyses indicated that this inhibition is not due to depletion of B or T cells but is instead dependent on signaling through ␤-adrenoceptors (␤ARs). We now show that impaired host resistance by CR cannot be accounted for by a decrease in LM-specific (listeriolysin O 91-99 tetramer ؉) effector CD8 ؉ T cells; this result is consistent with previous observations that CRinduced effects are mainly limited to early anti-LM responses. ␤2-Adrenoceptor (␤2AR) ؊/؊ FVB/NJ and wild-type FVB/NJ mice had equivalent anti-LM defenses, whereas ␤1-adrenoceptor (␤1AR) ؊/؊ FVB/NJ mice had lower levels of LM even when subjected to CR treatment. Additionally, host-resistance competency of ␤1AR ؊/؊ mice could be transferred to irradiated wild-type mice reconstituted with ␤1AR ؊/؊ bone marrow progenitors and spleen cells, indicating that ␤1AR signaling on immune cells reduces anti-LM responses. ␤1AR ؊/؊ mice had improved cellular (delayed-type hypersensitivity) responses while ␤2AR ؊/؊ mice had improved humoral responses (IgG1, IgG2, and IgM), a result that further explains the strain differences in LM defenses. CRinduced expression of ␤1AR and ␤2AR mRNA was assessed by real-time PCR. CR treatment significantly increased ␤AR mRNAs in Ficoll-purified and F4/80 ؉-enhanced liver but not splenic homogenates, demonstrating an organ-specific effect of stress that alters host defenses. Finally, CR treatment induced early increases in perforin expression that may enhance immune cell apoptosis and interfere with LM clearance. In conclusion, ␤1AR signaling has immunomodulatory effects on early cell-mediated immune responses; a lack of ␤1AR signaling improves antilisterial defenses and cell-mediated immunity, in general.