Prue Hart - Profile on Academia.edu (original) (raw)

Papers by Prue Hart

BMC Pregnancy and Childbirth, Feb 21, 2005

Background: Chorioamnionitis is a common underlying cause of preterm birth (PTB). It is hypothesi... more Background: Chorioamnionitis is a common underlying cause of preterm birth (PTB). It is hypothesised that polymorphisms in immunoregulatory genes influence the host response to infection and subsequent preterm birth. The relationship between histologic chorioamnionitis and 22 single nucleotide polymorphisms in 11 immunoregulatory genes was examined in a case-control study. Methods: Placentas of 181 Caucasoid women with spontaneous PTB prior to 35 weeks were examined for histologic chorioamnionitis. Polymorphisms in genes IL1A, IL1B, IL1RN, IL1R1, tumour necrosis factor (TNF), IL4, IL6, IL10, transforming growth factor beta-1 (TGFB1), Fas (TNFRSF6), and mannose-binding lectin (MBL2) were genotyped by polymerase chain reaction and sequence specific primers. Multivariable logistic regression including demographic and genetic variables and Kaplan-Meier survival analyses of genotype frequencies and pregnancy outcome were performed. Results: Sixty-nine (34%) women had histologic evidence of acute chorioamnionitis. Carriage of the IL10-1082A/-819T/592A (ATA) haplotype [Multivariable Odds ratio (MOR) 1.9, P = 0.05] and MBL2 codon 54Asp allele (MOR 2.0, P = 0.04), were positively associated with chorioamnionitis, while the TNFRSF6-1377A/-670G (AG) haplotype (MOR 0.4, P = 0.03) and homozygosity for TGFB1-800G/509T (GT) haplotype (MOR 0.2, P = 0.04) were negatively associated. These findings demonstrate that polymorphisms in immunoregulatory genes IL10, MBL2, TNFRSF6 and TGFB1 may influence susceptibility to chorioamnionitis. Acute infection of the amniotic fluid and chorioamnion is a common cause of preterm delivery before 34 weeks gestation. Consistent with previous reports [1], an Australian

Photochemical and Photobiological Sciences, Dec 1, 2018

The realisation that UV radiation (UVR) exposure could induce a suppressed immune environment for... more The realisation that UV radiation (UVR) exposure could induce a suppressed immune environment for the initiation of carcinogenesis in the skin was first described more than 40 years ago. Van der Leun and his colleagues contributed to this area in the 1980s and 90s by experiments in mice involving UV wavelength and dose-dependency in the formation of such tumours, in addition to illustrating both the local and systemic effect of the UVR on the immune system. Since these early days, many aspects of the complex pathways of UV-induced immunosuppression have been studied and are outlined in this review. Although most experimental work has involved mice, it is clear that UVR also causes reduced immune responses in humans. Evidence showing the importance of the immune system in determining the risk of human skin cancers is explained, and details of how UVR exposure can down-regulate immunity in the formation and progression of such tumours reviewed. With increasing knowledge of these links and the mechanisms of UVR-induced immunosuppression, novel approaches to enhance immunity to skin tumour antigens in humans are becoming apparent which, hopefully, will reduce the burden of UVR-induced skin cancers in the future.

The anti-inflammatory actions of IL-4 in human monocytes are not mediated by IL-10, RP105 or the kinase activity of RIPK2

Cytokine, Jun 1, 2012

The anti-inflammatory actions of IL-4 in activated human monocytes may reflect transcriptional re... more The anti-inflammatory actions of IL-4 in activated human monocytes may reflect transcriptional regulation of genes involved in TLR signaling pathways. Tailored gene arrays were conducted to profile the expression of 84 genes central to TLR-mediated signal transduction in human monocytes treated with the TLR4 ligand, LPS, with or without IL-4. In the first 3h, IL-4 down-regulated mRNA levels of LPS-induced inflammatory cytokines and chemokines, without altering mRNA levels of TLRs, TLR-related signaling molecules or multiple transcription factors. The down-regulation of inflammatory genes by IL-4 was preceded by an early up-regulation of IL-10 mRNA and protein and mRNA for receptor-interacting serine-threonine kinase 2 (RIPK2), the TLR homolog, RP105, and c-Maf, a transcription factor required for IL-10 gene expression. However, IL-4 still suppressed LPS-induced TNFα production in bone-marrow derived macrophages from IL10(-/-) mice, and in the presence of a neutralizing antibody to IL-10 in human monocytes. The up-regulation of RIPK2 and RP105 mRNA by IL-4 occurred independently of IL-10. IL-4 maintained the ability to suppress LPS-induced TNFα and enhance IL-10 production in the presence of RIPK2 kinase inhibitors. Further, IL-4 failed to up-regulate expression of RP105 at the cell surface. In conclusion, the anti-inflammatory actions of IL-4 occur independently of IL-10, RP105, and the kinase activity of RIPK2.

Immunology, Apr 1, 1999

Interleukin-4 (IL-4) is the prototypic type 2 immunoregulatory cytokine that can suppress the pro... more Interleukin-4 (IL-4) is the prototypic type 2 immunoregulatory cytokine that can suppress the production of many monocyte and macrophage pro-inflammatory mediators. In this study we investigated the regulation by IL-4 of IL-12 and IL-10 production. While IL-4 suppressed lipopolysaccharide (LPS )-induced IL-12 and IL-10 production by human peripheral blood monocytes, IL-4 suppressed LPS-induced IL-12, but not IL-10, production by synovial fluid mononuclear cells from patients with rheumatoid arthritis. IL-4 also suppressed IL-12, but not IL-10 production, by LPS-stimulated in vitro monocyte-derived macrophages. Similarly, IL-4 cannot suppress LPS-induced tumour necrosis factor-a (TNF-a) production by synovial fluid cells and monocyte-derived macrophages. The failure of IL-4 to regulate IL-10 production is not due to the failure of IL-4 to suppress TNF-a, and vice versa. The data suggest that the IL-4 receptor subunit, c c , is essential for IL-4 regulation of LPS-induced IL-10 production and that a correlation exists between duration of monocyte culture, reduction in c c mRNA in cultured cells and hyporesponsiveness of monocyte-derived macrophages to IL-4 for regulation of LPS-induced IL-10 production. This study highlights the importance of investigating responses to IL-4, as a potential therapeutic anti-inflammatory agent, by cells isolated from inflammatory sites and not by the more easily accessible blood monocytes. This study emphasizes the involvement of signalling from c c in IL-4 regulation of LPS-induced IL-10 production by monocytes and macrophages.

Pediatrics, 2015

Birth cohort studies provide an invaluable resource for studies of the influence of the fetal env... more Birth cohort studies provide an invaluable resource for studies of the influence of the fetal environment on health in later life. It is uncertain to what extent maternal vitamin D status influences fetal development. Using an unselected community-based cohort of 901 mother-offspring pairs (the Western Australian Pregnancy Cohort [Raine] Study), we examined the relationship between maternal vitamin D deficiency at 18 weeks' pregnancy and long-term health outcomes of offspring who were born in Perth, Western Australia (32°South), in 1989-1991. Vitamin D deficiency (serum 25-hydroxyvitamin D [25(OH)D] ,50 nmol/L) was present in 36% (323 of 901) of the pregnant women. After adjusting for relevant covariates, maternal vitamin D deficiency during pregnancy was associated with impaired lung development in 6-year-old offspring, neurocognitive difficulties at age 10, increased risk of eating disorders in adolescence, and lower peak bone mass at 20 years. In summary, vitamin D may have an important, multifaceted role in the development of fetal lungs, brain, and bone. Experimental animal studies support an active contribution of vitamin D to organ development. Randomized controlled trials of vitamin D supplementation in pregnant women with long-term follow-up of offspring are urgently required to examine whether the correction of vitamin D deficiency in pregnant women is beneficial for their offspring and to determine the optimal level of maternal serum 25(OH)D for fetal development.

Frontiers in Immunology, Jun 10, 2021

Cells of the skin and circulation are in constant two-way communication. Following exposure of hu... more Cells of the skin and circulation are in constant two-way communication. Following exposure of humans to sunlight or to phototherapy, there are alterations in the number, phenotype and function of circulating blood cells. In this review, only data obtained from human studies are considered, with changes induced by UV radiation (UVR) exposure described for phagocytic leukocytes and peripheral blood mononuclear cells plus their component T and B cells, natural killer cells and dendritic cells. These immune modulations illustrate the potential of UVR to have therapeutic effects beyond the skin, and that sunlight exposure is an important environmental influence on human health.

Incorporation of α-linolenic acid and linoleic acid into human respiratory epithelial cell lines

Lipids, Jul 1, 2001

Animal and human studies designed to examine the effects of α-linolenic acid (ALA) and linoleic a... more Animal and human studies designed to examine the effects of α-linolenic acid (ALA) and linoleic acid (LA) supplementation on the fatty acid composition of plasma and tissues have demonstrated a marked difference in incorporation into phospholipids of these 18-carbon precursors of the long-chain polyunsaturates. Whereas tissue phospholipid levels are linearly related to dietary ALA and LA, the levels of tissue LA can be 10-fold higher than tissue ALA even when dietary levels are equivalent. There is some dispute whether this disparity is due to ALA being more rapidly metabolized to its products or substantially oxidized by the liver, or whether LA but not ALA is readily incorporated into cellular phospholipids. We examined the level of incorporation of polyunsaturated fatty acids into human respiratory epithelial cell lines (A549, 16HBE) by determining the dose-dependent incorporation of ALA and LA as free fatty acid (5–150 μg FFA/mL). Cell membrane phospholipid ALA and LA were both increased up to ∼20–30% total fatty acids, with a concomitant decrease predominantly in monounsaturated membrane fatty acids, before significant toxicity was observed (50 μg/mL). Our data support the concept that rather than any inherent inability by human cells to incorporate ALA into membrane phospholipids, the lack of ALA content in human and animal tissues in vivo is due to the rapid metabolism or oxidation of this fatty acid in the liver.

Immunology, Dec 1, 1996

(IL-4), like interferon-y (IFN-y), stimulates monocyte major histocompatibility complex (MHC) cla... more (IL-4), like interferon-y (IFN-y), stimulates monocyte major histocompatibility complex (MHC) class II expression and thus, by increasing antigen presentation, has the potential to increase immune reactivity. In this study, activation of human monocytes by lipopolysaccharide (LPS) prevented concomitant IL-4 stimulation of MHC class II expression. However, this was not a general observation for activated monocytes because although the high levels of MHC class II antigen expressed by monocytes stimulated in vitro with IFN-y were not further regulated by IL-4, the stimulatory effects of IL-4 persisted on cells activated with granulocyte-macrophage colony- stimulating factor and tumour necrosis factor-a for enhanced MHC class II expression. MHC class II expression by monocytes cultured for 7 days with macrophage colony-stimulating factor was regulated by IL-4 and LPS in a manner very similar to that detected for freshly isolated monocytes. The inhibitory effect of LPS was not due to LPS-induced production of IL-1O or regulatory prostanoids. Furthermore, IFN-y-increased MHC class II expression was suppressed by LPS, suggesting that the regulation was at the level of MHC class II expression per se. This study suggests that during Gram-negative bacterial infections, IL-4 and IFN-y may not be able to signal enhanced MHC class II expression and thus, enhanced immune reactivity.

Journal of Immunological Methods, Jul 1, 2003

Due to their phagocytic and poorly proliferative nature, it has been difficult to transfect human... more Due to their phagocytic and poorly proliferative nature, it has been difficult to transfect human monocytes and macrophages. Adenoviral vectors have recently allowed transduction of a high percentage of human macrophages, but only after CSF upregulation of the integrins, avh3 or avh5, during culture for 48 h, a time allowing significant monocyte to macrophage differentiation. In our hands, after 24-h incubation with M-CSF (20 ng/ml) and a further 24-h incubation with an adenoviral vector encoding green fluorescent protein (AdV-GFP) [multiplicity of infection (MOI) = 50:1], only 35% of CD14-positive cells express GFP. We report that centrifugation of these cells with AdV-GFP at 2000 Â g for 1 h at 37 jC significantly enhanced the number of cells expressing GFP (to 65%) and the level of GFP expression per transduced cell (fivefold). The viability of the cells was not compromised ( < 5 % CD14-positive cells were 7-aminoactinomycin D (7AAD)-positive after 24 h AdV-GFP exposure at MOI = 50:1). Centrifugation allowed efficient transduction of monocytes and macrophages with an MOI at least tenfold lower than otherwise required and did not activate the transduced cells or affect their ability to produce TNFa or IL-1h in response to lipopolysaccharide (LPS). This methodology was also suitable for transducing large numbers of in vitro monocyte-derived macrophages (MDMac) and macrophages isolated from synovial fluids with up to 75 -80% of CD14positive cells transduced after 24-h exposure to AdV-GFP (50:1) and centrifugation (2000 Â g). This methodology should provide significant expression of transgenes in human monocytes and macrophages.

IL-4 suppresses IL-1 beta, TNF-alpha and PGE2 production by human peritoneal macrophages

PubMed, Mar 1, 1991

Human interleukin-4 (IL-4) down-regulates IL-1 and tumour necrosis factor-alpha (TNF-alpha) produ... more Human interleukin-4 (IL-4) down-regulates IL-1 and tumour necrosis factor-alpha (TNF-alpha) production by monocytes stimulated in vitro. In contrast, in studies of activation of murine macrophages, both stimulatory and inhibitory functions of murine IL-4 have been documented. To investigate whether opposing activities of IL-4 reflect a difference in the target cell studied, due either to cell maturation or the site from which the cells were isolated, we examined the effect of IL-4 on human peritoneal macrophage production of IL-1 beta, TNF-alpha and prostaglandin E2 (PGE2). Human peritoneal macrophages stimulated with lipopolysaccharide (LPS) produced levels of these mediators that were at least as great as those previously reported for monocytes. Similarly, IL-4 was inhibitory for peritoneal macrophage mediator production after in vitro stimulation. Thus, IL-4 has effects on human peritoneal macrophages similar to those on blood monocytes. In addition, as it down-regulates mediator production by cells that have left the circulation, it may be important in controlling the immune response in tissues.

Synovial fluid macrophages and blood monocytes differ in their response to IL-4

Journal of Immunology, Sep 15, 1993

IL-4 has been described as a potential anti-inflammatory molecule because of its ability in vitro... more IL-4 has been described as a potential anti-inflammatory molecule because of its ability in vitro to down-regulate human monocyte production of proinflammatory mediators. In this study, the activity of IL-4 on mononuclear cells and CD14+ macrophages from a site of chronic inflammation, namely, the joints of patients with rheumatoid and psoriatic arthritis, was investigated and compared directly with its activity on PBMC and monocytes from the same patients. In contrast to the response by blood monocytes, the response to IL-4 by synovial fluid cells was selective; IL-4 did not significantly suppress LPS-induced TNF-alpha production, but decreased CD14 expression to a similar extent in the two cell populations. IL-4 induction of monocyte/macrophage CD23 expression was investigated as a stimulatory response to IL-4, and although significantly increased on synovial fluid CD14+ cells by IL-4, the induction was considerably reduced compared with that measured for blood cells. Activation and differentiation in vitro of blood monocytes reduced their response to IL-4 for decreased TNF-alpha production and induction of CD23 and suggested that these biologic phenomena may contribute to the decreased responsiveness to IL-4 by synovial fluid monocytes/macrophages. Thus, IL-4 does not have the same anti-inflammatory properties in vitro on synovial fluid cells as on blood monocytes.

Drug Metabolism in Liver Disease

Gastroenterology, Oct 1, 1978

Antipyrine half-life (AP t1/2) was measured in 62 patients with, and 10 control patients without,... more Antipyrine half-life (AP t1/2) was measured in 62 patients with, and 10 control patients without, liver disease to ascertain possible factors which may be useful in identifying patients with abnormal drug metabolism. Antipyrine metabolism was normal or marginally impaired in patients with compensated cirrhosis or acute hepatitis, whereas it was frequently abnormal in those with chronic active hepatitis or advanced alcoholic liver disease. A high degree of correlation was found among AP t1/2 and prothrombin time, hepatic encephalopathy, and ascites. Of patients with severely impaired drug metabolism, 80% had one or more of these features. The severity of histological changes in liver biopsies was of additional help in predicting impaired drug metabolism. Concurrent drug ingestion enhanced antipyrine metabolism in most patients with liver disease as well as in control patients. Inadequate diet was associated with prolongation of AP t1/2, but other environmental factors such as alcohol ingestion, cigarette smoking, and coffee consumption did not affect rates of drug metabolism in patients with liver disease. Consideration of all of the above factors allows qualitative predictions of the rate of hepatic drug metabolism in patients with liver disease, as assessed by the AP t1/2.

Contrasting effects of interferon-gamma and interleukin-4 on the interleukin-6 activity of stimulated human monocytes

PubMed, Sep 1, 1990

Stimulated human monocytes/macrophages are a source of interleukin-6 (IL-6), which is a likely me... more Stimulated human monocytes/macrophages are a source of interleukin-6 (IL-6), which is a likely mediator involved in immune and inflammatory reactions. The means to control production of IL-6 by these cells could therefore have therapeutic applications. We report here, for lipopolysaccharide (LPS)-stimulated human monocytes in vitro, that the lymphokine, interferon-gamma (IFN-gamma) (100 U/ml), enhanced the level of IL-6 activity, whereas another lymphokine, interleukin-4 (IL-4) (greater than or equal to 0.1 U/ml; greater than or equal to 1.2 x 10(-11) M), suppressed it. The effects of the two lymphokines were manifested at the level of mRNA. The action of the IL-4 was similar to that of the glucocorticoid, dexamethasone, but observed at a lower molar concentration. Such regulation of monocyte IL-6 activity is similar to that found previously for interleukin-1 (IL-1) and tumour necrosis factor-alpha (TNF-alpha) synthesis.

Comparison of the suppressive effects of interleukin-10 and interleukin-4 on synovial fluid macrophages and blood monocytes from patients with inflammatory arthritis

PubMed, Apr 1, 1995

This study determined the potential capacity of interleukin-10 (IL-10), compared with IL-4, to co... more This study determined the potential capacity of interleukin-10 (IL-10), compared with IL-4, to control the production of tumour necrosis factor-alpha (TNF-alpha), IL-1 beta and IL-1 receptor antagonist (IL-1ra) and the expression of major histocompatibility complex (MHC) class II antigens by monocytes/macrophages isolated from synovial fluid of patients with rheumatoid or other forms of chronic inflammatory arthritis. Mononuclear cells were isolated from synovial fluid and peripheral blood and incubated with or without lipopolysaccharide (LPS), and with or without IL-10 (100 U/ml, 10 ng/ml) or IL-4 (10 ng/ml) for 22 hr. TNF-alpha, IL-1 beta and IL-1ra levels were measured by enzyme-linked immunosorbent assay (ELISA) in the culture supernatants, and MHC class II expression was examined on the monocytes/macrophages by flow cytometry. IL-10, unlike IL-4, decreased TNF-alpha production by LPS-stimulated synovial fluid cells to the same extent as by LPS-stimulated peripheral blood cells from the same patients. IL-10 and IL-4 suppressed equally IL-1 beta production by the same cells. However, only IL-4 significantly increased IL-1ra production by synovial fluid mononuclear cells. Synovial fluid cells expressed increased levels of MHC class II antigen, and these levels were not as efficiently suppressed by IL-10 as they were for peripheral blood cells. Because IL-10 and IL-4 differentially regulate TNF-alpha and IL-1ra production by synovial fluid mononuclear cells, selective use of either IL-10 or IL-4 in the treatment of chronic inflammatory conditions will depend on whether TNF-alpha or IL-1, respectively, is established as primarily responsible for the maintenance of the chronic inflammatory condition.

Journal of Investigative Dermatology, Aug 1, 2000

Ultraviolet B radiation (280±320 nm) can initiate skin cancer as well as suppress the immune syst... more Ultraviolet B radiation (280±320 nm) can initiate skin cancer as well as suppress the immune system, thereby preventing the rejection of ultraviolet-Binduced tumors. Recently we reported that there was not only a correlation but also a functional link between dermal mast cell prevalence and susceptibility to ultraviolet-B-induced systemic immunosuppression in multiple strains of mice. In this study, we investigated whether increased dermal mast cell prevalence is a signi®cant predisposing factor for basal cell carcinoma development in humans. In 21 Danes with a history of basal cell carcinoma and 20 control subjects of similar age, sex, skin phototype, and recreational sun exposure over the past 12 mo, dermal mast cell prevalence was quanti®ed on nonsun-exposed buttock skin. We investigated this skin site in order to avoid any changes in mast cell prevalence caused by sun exposure and assumed that the prevalence of mast cells in buttock skin correlated with that at sun-exposed sites at critical times in the development of basal cell carcinomas. Patients with a history of basal cell carcinoma had a signi®cantly higher median dermal mast cell prevalence than control subjects (p = 0.01, Mann±Whitney U ). No correlation was observed between dermal mast cell prevalence and age of basal cell carcinoma patients and control subjects. These results suggest that increased dermal mast cell prevalence is a predisposing factor for basal cell carcinoma development in humans. We hypothesize that mast cells function in humans, as in mice, by initiating immunosuppression and thereby allowing a permissive environment for basal cell carcinoma development.

Journal of Investigative Dermatology, Nov 1, 2003

Cutaneous exposure to ultraviolet (UV) A (320^400 nm) results in the formation of damaging reacti... more Cutaneous exposure to ultraviolet (UV) A (320^400 nm) results in the formation of damaging reactive oxygen intermediates, which are implicated as mediators of DNA damage, apoptosis, and photoaging. S100A8 is a low-molecular-weight calcium-binding protein, highly sensitive to oxidation. In this study, UVA-induced S100A8 expression by keratinocytes was investigated. UVA (50^100 kJ per m 2 ) strongly induced S100A8 in differentiated keratinocytes in the epidermis of BALB/c mice. Similarly, S100A8 mRNA and monomeric protein were signi¢cantly upregulated in PAM212 cells (a murine keratinocyte cell line) in response to 10 kJ per m 2 UVA 24 h after irradiation. Although S100A9 associ-ates with S100A8 in neutrophils and abnormally di¡erentiated keratinocytes (human psoriasis), in this study it was not coinduced with keratinocyte S100A8. Dorsal application of 4-hydroxy-tempo (a superoxide dismutase-mimicking agent) to mice concentrationdependently reduced UVA-induced S100A8 expression. Incubation of PAM212 cells with superoxide dismutase and catalase during UVA irradiation also abrogated S100A8 induction. These results suggest that UVA-induced S100A8 is expressed by keratinocytes in response to generation of reactive oxygen intermediates. Key words: singlet oxygen/superoxide enzymes/S100 proteins. J Invest Dermatol 121:1168 ^1174, 2003 U ltraviolet (UV) radiation triggers rapid induction of sets of genes (including those involved in oxidative defense) that are protective, particularly against UV-induced DNA damage. Responses to UVA irradiation (320^400 nm) of the skin are predominantly mediated by oxygen-dependent processes via the formation of reactive oxygen intermediates (ROI), including the superoxide anion (O 2 Á ^), the hydroxyl radical, hydrogen peroxide (H 2 O 2 ), and singlet molecular oxygen. ROI oxidize a large range of biologic molecules, causing damage to cellular membrane lipids, proteins, and DNA . UVA-induced ROI promote apoptosis and activate numerous proteins with antioxidant and free-radical-scavenging properties involved in the cellular stress response . Keratinocytes, located in the outermost layer of the skin, contain higher than normal levels of antioxidants including glutathione and enzymes involved in antioxidant defense. These include superoxide dismutase (SOD), a radical scavenger of O 2 Á ^that catalyzes dismutation of O 2 Á ^to O 2 and H 2 O 2 (Trenam et al, 1992), and catalase, which converts H 2 O 2 to H 2 O and O 2 . Nevertheless, as may occur in in£ammation, high levels of ROI generated by UVA could overwhelm normal defenses to oxidative damage so that additional protective responses are provoked.

Immunology and Cell Biology, Apr 1, 2001

In airways, mast cells lie adjacent to nerves, blood vessels and lymphatics, which highlights the... more In airways, mast cells lie adjacent to nerves, blood vessels and lymphatics, which highlights their pivotal importance in regulating allergic inflammatory processes. In asthma, mast cells are predominantly activated by IgE receptor cross linking. In response to activation, preformed mediators that are stored bound to proteoglycans, for example, TNF-α, IL-4, IL-13, histamine, tryptase and chymase, are released. New synthesis of arachidonic acid metabolites (leukotriene C4 (LTC4), leukotriene B4 (LTB4) and prostaglandin D2 (PGD2)) and further cytokines is stimulated. Mediators from degranulating mast cells are critical to the pathology of the asthmatic lung. Mast cell proteases stimulate tissue remodelling, neuropeptide inactivation and enhanced mucus secretion. Histamine stimulates smooth muscle cell contraction, vasodilatation and increased venular permeability and further mucus secretion. Histamine induces IL-16 production by CD8 + cells and airway epithelial cells; IL-16 is an important early chemotactic factor for CD4 + lymphocytes. LTC4, LTB4 and PGD2 affect venular permeability and can regulate the activation of immune cells. The best characterized mast cell cytokine in asthmatic inflammation is TNF-α, which induces adhesion molecules on endothelial cells and subsequent transmigration of inflammatory leucocytes. IL-13 is critical to development of allergic asthma, although its mode of action is less clear.

American Journal of Respiratory Cell and Molecular Biology, Nov 1, 2015

We have previously demonstrated increased airway smooth muscle (ASM) mass and airway hyperrespons... more We have previously demonstrated increased airway smooth muscle (ASM) mass and airway hyperresponsiveness in whole-life vitamin D-deficient female mice. In this study, we aimed to uncover the molecular mechanisms contributing to altered lung structure and function. RNA was extracted from lung tissue of whole-life vitamin D-deficient and -replete female mice, and gene expression patterns were profiled by RNA sequencing. The data showed that genes involved in embryonic organ development, pattern formation, branching morphogenesis, Wingless/Int signaling, and inflammation were differentially expressed in vitamin D-deficient mice. Network analysis suggested that differentially expressed genes were connected by the hubs matrix metallopeptidase 9; NF-k light polypeptide gene enhancer in B cells inhibitor, a; epidermal growth factor receptor; and E1A binding protein p300. Given our findings that developmental pathways may be altered, we investigated if the timing of vitamin D exposure (in utero vs. postnatal) had an impact on lung health outcomes. Gene expression was measured in in utero or postnatal vitamin D-deficient mice, as well as whole-life vitamin D-deficient and -replete mice at 8 weeks of age. Baseline lung function, airway hyperresponsiveness, and airway inflammation were measured and lungs fixed for lung structure assessment using stereological methods and quantification of ASM mass. In utero vitamin D deficiency was sufficient to increase ASM mass and baseline airway resistance and alter lung structure. There were increased neutrophils but decreased lymphocytes in bronchoalveolar lavage. Expression of inflammatory molecules S100A9 and S100A8 was mainly increased in postnatal vitamin D-deficient mice. These observations suggest that in utero vitamin D deficiency can alter lung structure and function and increase inflammation, contributing to symptoms in chronic diseases, such as asthma.

Clinical and Experimental Immunology, Mar 1, 1995

Activated macrophages are central to the destructive processes of chronic inflammatory arthritis.... more Activated macrophages are central to the destructive processes of chronic inflammatory arthritis. In this study, it was hypothesized that IL-13, a product predominantly of 'Th2-type' lymphocytes, may be used therapeutically to down-regulate monocyte/macrophage activities at sites of chronic inflammation. Synovial fluid mononuclear cells were isolated from 12 patients with chronic inflammatory arthritis. Peripheral blood mononuclear cells (PBMC) were isolated at the same time as synovial fluid cells from all 12 patients. IL-13 significantly inhibited lipopolysaccharide (LPS)-induced tumour necrosis factor-alpha (TNF-a) production by mononuclear cells from peripheral blood, but not synovial fluid. In contrast, IL-13 inhibited LPS-induced IL-1,/ production by all cells, and as a positive response to IL-13, CD23 expression was increased on both cell populations. Blood monocytes cultured for 7 days with granulocyte-macrophage colony- stimulating factor (GM-CSF) or M-CSF responded to IL-1 3 in a manner similar to that detected for synovial fluid-derived cells, with suppression of LPS-induced IL-1,i, but not TNF-a, production. In all experiments, the responses to IL-13 were very similar to those detected to IL-4, but differed from those measured with IL-10. Thus, the responses to IL-13 by synovial fluid cells and cultured monocytes are not equal to those of blood monocytes. The similar responses to IL-4 and IL-13 support claims of a common element for signalling from the IL-4 and IL-13 receptors. Furthermore, the activity of a common receptor chain may be altered by monocyte activation and differentiation.

Benefits of vitamin D for allergic airways

Clinical & Experimental Allergy, May 28, 2013