The acute and sensitization effects of tumor necrosis factor-α: implications for immunotherapy as well as psychiatric and neurological conditions (original) (raw)
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Neuroscience, 1998
Despite a vast amount of research into the actions of cytokines within the central nervous system, the pharmacological role and/or physiological function of the various cytokines within the central nervous system is still not fully understood. The present study evaluated the effects of intracerebroventricular administration of interleukin-1 , -2, -6 (20 ng) and tumour necrosis factor-(40 ng) on elevated plus maze behaviour, monoamine levels in the hypothalamus, hippocampus and amygdala, plasma corticosterone and catecholamine concentrations and Concanavalin A-induced splenic lymphocyte proliferation in the rat. Both interleukin-1 and tumour necrosis factor-induced ''anxiogenic-like'' effects on the elevated plus maze, whereas interleukin-2 and interleukin-6 did not. However only interleukin-1 led to endocrine variations often associated with stress and anxiety. Cytokine specific alterations in monoamine levels were evident in the hypothalamus and hippocampus, while neurotransmitter concentrations in the amygdala were not significantly altered by cytokine treatment. In addition, interleukin-1 reduced Concanavalin A-induced lymphocyte proliferation, whereas the other cytokine treatments failed to significantly alter this response. These results demonstrate that in some, but not all, respects interleukin-1 administration produced ''stress like'' effects on behaviour, monoamine neurotransmitters, hypothalamic-pituitary-adrenal axis activity and immune function, while the other cytokines produced less consistent effects on these parameters.
Cytokines as a stressor: implications for depressive illness
The international journal of neuropsychopharmacology / official scientific journal of the Collegium Internationale Neuropsychopharmacologicum (CINP), 2002
Stressful events have been implicated in the provocation of depressive illness. Inasmuch as immunological challenge, and particularly cytokine administration, engender neuroendocrine and central neurochemical changes reminiscent of those provoked by psychogenic stressors, it was suggested that immune activation may also contribute to affective illness. The present report provides a brief overview of the neurochemical sequelae of acute and repeated interleukin-1beta (IL-1beta), tumour necrosis factor-alpha (TNF-alpha) and IL-2 treatment, describes some of the synergisms associated with these treatments, as well as their potential interactions with psychogenic stressors. In addition, a discussion is provided concerning the fact that cytokines, like stressors, may have time-dependent proactive effects, so that re-exposure to the treatments provoke greatly augmented neurochemical changes (sensitization). Given that the effects of cytokines are evident within hypothalamic, as well as ext...
The Journal of Neuroscience, 1999
Consistent with the proposition that cytokines act as immunotransmitters between the immune system and the brain, systemic administration of the proinflammatory cytokine tumor necrosis factor-α (TNF-α; 1.0–4.0 μg) induced mild illness in CD-1 mice, increased plasma corticosterone concentrations, and altered central norepinephrine, dopamine, and serotonin turnover. The actions of TNF-α were subject to a time-dependent sensitization effect. After reexposure to a subeffective dose of the cytokine (1.0 μg) 14–28 d after initial treatment, marked illness was evident (reduced consumption of a palatable substance and diminished activity and social exploration), coupled with an elevation of plasma corticosterone levels. In contrast, cytokine reexposure 1–7 d after initial treatment did not elicit illness, and at the 1 d interval the corticosterone response to the cytokine was reduced. The increase of norepinephrine release within the paraventricular nucleus of the hypothalamus, as reflected...
Interaction Between Inflammatory State and Neurochemical Changes in Major Psychiatric Disorders
In 1975, Ader and Cohen reported that immune suppression could be induced by behavioural condition (Ader and Cohen, 1975). That was the clear demonstration that peripheral immune system could be influenced by emotion or behavioural manipulation. In the following years, the body and brain crosstalk through immune system became of interest in pathophysiology of psychiatric disorders. In 1987, the low natural killer cell activity in patients with depression was reported (Irwin et al., 1987). In early 1990s "sickness behaviour" was proposed as peripheral immune activation induced depressive like behaviour based on the fact that injection of bacterial toxin, lipopolysaccharide, peripherally could induce depressive like behaviour (Bluthe et al., 1992). They also reported that sickness behaviour induced by peripheral immune activation was reversed by administering the antagonist of interleukin-1 (IL1) receptor. While sickness behaviour is, unlike major depressive disorders, a short term syndrome, the symptoms of sickness behaviour such as lack of interest, inability to concentrate, loss of appetite, disturbance of sleep and social anhedonia are the similar symptoms as in depression. Thus, immune activation in the periphery was considered as part of the pathophysiological mechanisms of major depression and anti inflammatory medication or manipulation of immune system became of new therapeutic interest. The first theory on the immune activation in psychiatric disorders proposed was "macrophage theory of depression" (Smith, 1991) in which the association between cytokine secreted from macrophage and hypothalamus activity were proposed as pathophysiological mechanism of major depressive disorder. This theory has highlighted the interaction between immune system and endocrine system which could influence the emotion and higher function of the human brain. Based on the finding related to the connection between lymphocyte function, hypothalamo-hypophysial-adrenal axis and depression which indicated the impaired lymphocyte response to mitogen stimulation (Maes et al., 1989), the macrophage theory of depression was extended to monocyte-lymphocyte hypothesis of depression (Maes et al., 1995). The same authors have also extended the hypothesis to another major psychiatric disorder, schizophrenia (Smith and Maes, 1995). It was discussed that the cytokines, such as, IL1 and IL2 in low concentration could enhance the dopaminergic neurotransmission whereas high IL2 could suppress it. Around this period, the impairment of neutrophil and macrophage phagocytoses in depressed patients was also reported (McAdams and Leonard, 1993). Changes in immunoglobulin, complement and acute phase protein levels were also reported in patients with depression (Song et al., 1994). Also in late 1080s, Nishino and colleagues has first demonstrated the prostaglandin E2 (PGE2), an enzyme involved in inflammatory process is increased in the saliva of depressed patients (Nishino et al., 1989). Based on the different subtypes of immune cells, some studies explore the ratios between different subsets of T-lymphocytes and demonstrated the higher T-helper/T-suppressor cytotoxic cell ratio in depressed patients (Maes et al., 1992). The enhanced T-helper type 1 immune response which is associated with development of inflammation was proposed in major depressive disorders. Similar development in research related to inflammatory response and schizophrenia also occur around this later 20 th Century and the beginning of 21 st Century. The increased T-helper type 2 cells in the blood of patients with schizophrenia were reported and the dominance of T-helper type 2 reaction was suggested (Spernerwww.intechopen.com Interaction Between Inflammatory State and Neurochemical Changes in Major Psychiatric Disorders 167 Unterweger et al., 1999). Based on this finding "Th-2 hypothesis of schizophrenia" was proposed (Schwarz et al., 2001). Around the same period in the beginning of 21 st Century, the tryptophan degradation induced by the indoleamine 2,3-dioxygenase (IDO) enzyme in the presence of inflammatory state became of interest as a link between immune function and serotonergic abnormalities due to reduced tryptophan availability (Capuron et al., 2002; Maes et al., 2002). A year later, the possible involvement of downstream tryptophan metabolites in terms of neurotoxic changes in major depressive disorders and further immune system and NMDA-glutermatergic neurotransmission interaction were proposed in "neurodegeneration hypothesis of depression" (Myint and Kim, 2003). Several therapeutic strategies have been studied in the area of immune activation and psychiatric disorders. The antagonist of pro-inflammatory cytokine such as tumour necrosis factor- (TNF), eternacept, and n3 fatty acids are those studied and given some promising results. Recently, add-on therapy with inhibitor of cyclooxygenase-2 (COX-2) enzyme, celecoxib which was originally an anti-inflammatory medication was reported to enhance the response to both anti-depressant therapy and anti-psychotic therapy. Moreover, the possible use of inflammatory based biomarkers in diagnosis and choice of medication in major psychiatric disorders are considered. In this chapter, brief basic immunology on inflammation, findings and mechanisms related to inflammatory state in psychiatric disorders, the immune-endocrine interaction, immuneendocrine-tryptophan metabolism interaction and inflammation-tryptophan metabolismneurochemicals interaction network were explained and discussed. 2. Inflammatory state 2.1 A short survey of the body's defence system The body's defense system is a complex arrangement of physical, chemical, biochemical, and cellular barriers. Here we will focus on immunity, which is the result of the interplay between two "immune" systems: the innate immune system, which is phylogenetically older, and the adaptive immune system of T and B cells (Medzhitov and Janeway-CA, 1998). The innate immune system functions in an antigen-nonspecific way, while antigen-specific mechanisms are mediated by the adaptive one. Characteristic cells of the innate immune system are e.g. granulocytes, natural killer (NK) cells, monocytes/macrophages, or dendritic cells. The innate immune system is the first line of defense against infection and it provides signals for the activation of the adaptive immune system. Innate responses serve to regulate the onset, duration, magnitude, and character of the antibody-and cell-mediated adaptive response. In contrast to the adaptive immune system, the innate immune system is not able to confer long-lasting memory, i.e. immunity against a specific pathogen. In the late 1980s, Janeway proposed the model of the antigen-presenting cells, which are able to recognize and differentiate distinct groups of microbes by special receptors, the socalled pattern-recognition receptors (Janeway, Jr., 1989). The identification of pathogenassociated molecular patterns or microbe-associated molecular patterns by the innate immune system allows the body's defense system to discriminate between "infectious nonself" and "non-infectious self". This concept was expanded by Matzinger's hypothesis of danger signals as inducers of the body's defense system (Matzinger, 1994). According to this new concept, immunological phenomena like autoimmunity, sterile inflammation, or the acceptance of the fetus, who is immunologically 50% non-self, by the mother's immune system can be explained. Matzinger proposed that antigen presenting cells are not activated
European Journal of Neuroscience, 2002
Systemic administration of murine tumour necrosis factor-a (mTNF-a; 0.1±2.0 mg, i.p.) dose-dependently increased plasma corticosterone and augmented monoamine utilization within the paraventricular nucleus of the hypothalamus (PVN), locus coeruleus, medial prefrontal cortex (PFC), central and medial amygdala. A time-dependent sensitization was induced in mice, wherein reexposure to mTNF-a 28 days (but not 1 day) following the initial cytokine treatment provoked marked signs of illness (diminished activity, ptosis, piloerection) and increased plasma corticosterone levels. Serotonin (5-HT) activity was augmented upon mTNF-a reexposure at the 1-or 28-day intervals in the PFC and medial amygdala, respectively. Intracerebroventricular (i.c.v.; 1±500 ng) mTNF-a did not promote illness, but modestly increased plasma corticosterone levels. Neither the illness nor the corticosterone changes were subject to a sensitization upon i.c.v. cytokine reexposure. Acute i.c.v. mTNF-a increased norepinephrine (NE), 5-HT and dopamine (DA) activity within the PVN and median eminence/arcuate nucleus complex (ME/ ARC), and NE utilization within the central amygdala. Subsequent i.c.v. mTNF-a further enhanced the hypothalamic monoamine variations. Finally, systemic (i.p.) mTNF-a pretreatment did not proactively in¯uence sickness or corticosterone responses upon later i.c.v. cytokine challenge, but augmented locus coeruleus NE activity and 5-HT and DA utilization within the ME/ARC. It is suggested that the sensitization with respect to sickness and corticosterone activity in response to mTNF-a re¯ect the involvement of peripheral mechanisms. Moreover, it appears that mTNF-a promotes central neurochemical plasticity through independent central and peripheral mechanisms.
Neurochemical and behavioral responses to inflammatory immune stressors
Frontiers in Bioscience, 2009
Introduction 3. Cytokine influences on the central nervous system 3.1. Cytokines within the brain 3.2. Neurochemical effects of cytokines 3.3. Synergies associated with cytokine treatments 3.4. Sensitization of cytokine-provoked neuronal processes 4. Behavioral Effects Associated With Cytokines-Animal Studies 4.1. Sickness Behaviors 4.2. Depressive-like features elicited in response to pro-inflammatory factors 4.3. Processes governing cytokine-induced behavioral variations 5. Inflammatory factors associated with depression in humans 5.1. Cytokine and acute phase protein correlates in patients with depressive disorders 5.2. Depressive symptoms in relation to allergies, chronic inflammatory diseases and cancer 5.3. Depressive disorder induced by IFN-alpha activation 5.4.Cognitive disturbances associated with cytokine (IFN) immunotherapy 6. Inflammatory processes in relation to neuropsychiatric manifestations in pathological conditions other than depression 6.1. Confusional states and cognitive disturbances in relation to acute inflammation and surgical insult 6.2. Inflammation and cognitive decline in non-demented elderly and in demented patients 6.3 Immune activation and neuropsychiatric symptoms in schizophrenia 7. Summary and perspective 8. Acknowledgment 9. References
The international journal of neuropsychopharmacology / official scientific journal of the Collegium Internationale Neuropsychopharmacologicum (CINP), 2002
Several lines of evidence indicate that cytokine-mediated communication pathways between the immune system and the brain are involved in the pathophysiology of depression: (1) . Depression is highly prevalent in various medical conditions, including infectious, autoimmune and neurodegenerative diseases. This clinical association cannot be attributed solely to psychological distress, and it probably reflects direct activation of illness-induced physiological processes. (2). Experiments in humans and in animals demonstrate that exposure to cytokines induces depressive-like mood and behavioural alterations. (3). Cytokine immunotherapy in cancer and hepatitis patients elicits a major depressive episode in a large percentage of the patients. (4). Several types of depression that are not directly associated with a physical disease (e.g. major depression, melancholia, dysthymia) were also associated with cytokine hypersecretion. (5). Antidepressant drugs possess anti-inflammatory character...
Treatment of cytokine-induced depression
Brain, Behavior, and Immunity, 2002
A high proportion of cancer and hepatitis C patients who receive cytokine immunotherapy develop symptoms of depression that are indistinguishable from those found in major depressive disorders. These symptoms are alleviated by anti-depressant treatment. Moreover, preventive treatment with anti-depressants, in particular selective serotonin reuptake inhibitors (SSRIs) attenuates IFN-a-associated symptoms of depression, anxiety, and neurotoxicity. The intermediate mechanisms of these effects are still unclear. Studies suggest that the state of depression is associated with an increase in plasma levels of various cytokines and soluble cytokine receptors. Furthermore, anti-depressants have been shown to shift the cytokine network towards a decreased production of pro-inflammatory cytokines and an increased production of anti-inflammatory cytokines. Other studies suggest that anti-depressants can also modify immune reactivity by acting on neural structures involved in neuroimmunomodulation. It is possible that anti-depressants could help to normalize the serotoninergic neurotransmission that is likely disrupted during immunotherapy due to the potent effects of cytokines on the metabolism of the amino acid precursor tryptophan. Further work is needed to optimize strategies for preventing neuropsychiatric side effects of cytokine immunotherapy, to clarify the mechanisms involved in the alleviating effects of anti-depressants on cytokine-induced depression, as well as to assess the possible consequences of anti-depressant therapy on the efficacy of immunotherapy on the disease process.
Inflammation and Its Discontents: the Role of Cytokines In the Pathophysiology of Major Depression
Biological psychiatry, 2009
Recognition that inflammation may represent a common mechanism of disease has been extended to include neuropsychiatric disorders including major depression. Patients with major depression have been found to exhibit increased peripheral blood inflammatory biomarkers, including inflammatory cytokines, which have been shown to access the brain and interact with virtually every pathophysiologic domain known to be involved in depression, including neurotransmitter metabolism, neuroendocrine function, and neural plasticity. Indeed, activation of inflammatory pathways within the brain is believed to contribute to a confluence of decreased neurotrophic support and altered glutamate release/reuptake, as well as oxidative stress, leading to excitotoxicity and loss of glial elements, consistent with neuropathologic findings that characterize depressive disorders. Further instantiating the link between inflammation and depression are data demonstrating that psychosocial stress, a well-known precipitant of mood disorders, is capable of stimulating inflammatory signaling molecules, including nuclear factor kappa B, in part, through activation of sympathetic nervous system outflow pathways. Interestingly, depressed patients with increased inflammatory biomarkers have been found to be more likely to exhibit treatment resistance, and in several studies, antidepressant therapy has been associated with decreased inflammatory responses. Finally, preliminary data from patients with inflammatory disorders, as well as medically healthy depressed patients, suggest that inhibiting proinflammatory cytokines or their signaling pathways may improve depressed mood and increase treatment response to conventional antidepressant medication. Translational implications of these findings include the unique opportunity to identify relevant patient populations, apply immune-targeted therapies, and monitor therapeutic efficacy at the level of the immune system in addition to behavior.