In mice, production of plasma IL-1 and IL-6 in response to MPTP is related to behavioral lateralization.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) induces dopaminergic neuron death in substantia nigra and dopamine loss in striatum, similar to those observed in Parkinson disease. Given MPTP can also induce alterations in brain cytokines and in peripheral immune parameters, we hypothesize that MPTP can induce an elevation of plasma cytokines. We have previously shown that cytokine production depends on behavioral lateralization in certain conditions. Therefore, we further postulate that the MPTP-induced plasma cytokines are related to behavioral lateralization. To answer these questions, C57BL/6J male mice, selected for paw preference, were injected with 25 mg/kg MPTP ip for five consecutive days and were decapitated at day 1, day 3, or day 14 after the last injection. Striatal DA and DOPAC concentration were measured by HPLC and plasma levels of IL-1beta and IL-6 were quantified by ELISA. The results showed that after MPTP treatment, striatal DA content was dramatically decreased, IL-1beta levels increased on day 3, while IL-6 levels increased on day 14. Interestingly, behavioral lateralization influenced DA/DOPAC ratio as well as plasma IL-1beta and IL-6 levels. In left-pawed mice, MPTP induced a higher decrease of DA/DOPAC ratio than in right-pawed mice. The increase of IL-1beta was observed in left-pawed but not in right-pawed mice. The elevation of IL-6 was higher in right-pawed mice than in left-pawed mice. These results have clearly demonstrated our hypotheses, that MPTP can induce increase of plasma IL-1beta and IL-6 levels in mice, and this effect is shaped by behavioral lateralization.

Asymmetrical distribution of brain interleukin-6 depends on lateralization in mice.

The central nervous system can regulate the peripheral immune system. Moreover, differences between left and right hemispheres (neurochemical brain asymmetries) and behavioral lateralization (functional brain asymmetries) affect immune responses. The molecular basis of brain-immune interactions remains insufficiently understood. Cytokines regulate immune responses, possibly through activation of the hypothalamic-pituitary-adrenal (HPA) axis. HPA axis activities are related to behavioral lateralization and brain asymmetry. Given IL-6 plays a role in asymmetrical brain immunomodulation, one might expect the IL-6 distribution in brain to be asymmetrical and to depend on behavioral lateralization. In order to start to test this hypothesis, male C57BL/6J mice were selected for paw preference and assessed for IL-6 levels in right and left cortex and hippocampus by enzyme linked immunosorbent assay. The results showed asymmetrical distribution of brain IL-6 in left-pawed animals and ambidextrous animals, but not in right-pawed animals, both in cortex and hippocampus. Furthermore, we found a correlation between IL-6 hemispheric distribution and the degree of behavioral lateralization both in cortex and hippocampus. Altogether, these results suggest that brain IL-6 could be a mediator of asymmetrical immunomodulation by the central nervous system.

Interleukine-1beta and interleukine-6 levels in striatum and other brain structures after MPTP treatment: influence of behavioral lateralization.

MPTP (N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) induces diminution of the dopamine in nigrostriatal pathway and cognitive deficits in mice. MPTP treatment also increases pro-inflammatory cytokine production in substantia nigra and striatum. Since, pro-inflammatory cytokines influence striatal dopamine content and provoke cognitive impairments, the cognitive defects induced by MPTP may be partly due to brain cytokine induction in other structures than nigrostriatal pathway. Furthermore, behavioral lateralization, as assessed by paw preference, influences cytokine production at the periphery and in the central nervous system. Behavioral lateralization may thus influence brain cytokine levels after MPTP. In order to address these issues, mice selected for paw preference were injected with 25 mg/kg MPTP i.p. for five consecutive days after which striatal dopamine and DOPAC contents were measured by HPLC and IL-1beta and IL-6 quantified by ELISA in the striatum, cerebral cortex, hippocampus and hypothalamus. The results showed that MPTP treatment induced dramatic loss of DA in striatum, simultaneously, IL-6 levels decreased in the striatum and increased in hippocampus and hypothalamus, while IL-1beta levels decreased in the striatum, cerebral cortex and hippocampus. Interestingly, striatal dopamine turnover under basal conditions as well as striatal IL-1beta and IL-6 levels under basal conditions and after MPTP depended on behavioral lateralization. Left pawed mice showed a higher decrease in dopamine turnover and lower cytokine levels as compared to right pawed animals. Behavioral lateralization also influenced IL-6 hippocampal levels under basal conditions and IL-1beta cortical levels after MPTP. From these results, it can be concluded that MPTP-induced cognitive defects are accompanied by an alteration of pro-inflammatory cytokine levels in brain structures other than those involved in the nigrostriatal pathway. In addition, MPTP-induced dopamine decrease is influenced by behavioral lateralization, possibly through an effect on brain cytokine levels.

Immune alterations induced by social defeat do not alter the course of an on-going BCG infection in mice.

The timing for applying stressor and primary immunization is known to influence the nature of the immune alterations induced by stress. The aim of the present study was to investigate the consequences of a stress occurring several days after the beginning of a primary infection on the host resistance. For this purpose, we investigated the effects of repeated social defeat on the immune response of mice infected with BCG 11 days before. In vitro production of cytokines in response to LPS or tuberculin, and the sensitivity of spleen cells to corticosterone were assessed 8 days after the end of the stress. Bacterial growth was assessed in the spleen. We demonstrated that social defeat in BCG-infected mice induced a long-term increase in IL-6 and IL-10 production in response to LPS but did not modify the sensitivity of spleen cells to corticosterone. Stress did not affect the specific response to BCG, as shown by the production of cytokines in tuberculin-stimulated cultures. Accordingly, social defeat was unable to influence the mycobacterial growth in vivo. These results support the hypothesis postulating that stress does not affect antigen-specific response when it is applied after priming.

The rank assessed in a food competition test influences subsequent reactivity to immune and social challenges in mice.

The purpose of this study was to investigate whether, in a stable social environment, social interactions are responsible for individual, endocrine and immune differences among group members. Cage-mates were classified according to their rank in a food competition test. The influence of the rank was evaluated in two different situations activating neuroendocrine and immune systems. A first experiment used a context of repeated social stress. A second experiment investigated the influence of rank on the response to a bacterial infection by BCG. Endocrine and immune functions were assessed by measuring plasma corticosterone levels, splenocyte proliferation and in vitro cytokine production. In control undisturbed groups, plasma levels of corticosterone were lower in low ranking (LR) mice than in intermediate (IR) and high ranking (HR) mice. LPS-induced splenocyte proliferation and in vitro cytokine production were independent of rank. In response to social stress, corticosterone increased similarly in all categories but the increase in splenocyte proliferation was more pronounced in HR animals. During BCG infection, the rank influenced the production of IL-10 and IFN-gamma by tuberculin-stimulated splenocytes during the acute phase of the infection but not after 94 days of infection. Cytokine production in response to LPS and bacterial growth were not affected by the rank. Therefore, social interactions emerging in a stable social group may be involved in the individual differences observed in endocrine activity and in immune system reactivity.

Role of cerebral lateralization in control of immune processes in humans.

Cerebral lateralization may be important in neural control of immune function. Animal studies have demonstrated differential effects of left and right brain lesions on immune function, but human studies are inconclusive. Here, we show that resections in the language dominant hemisphere of patients with epilepsy reduce lymphocytes, total T cells, and helper T cells. In contrast, resections in the language nondominant hemisphere increased the same cellular elements. T-cell responses to mitogens and microbial antigens were not differentially affected. Left/right arm histamine skin response ratios were altered in patients with left cerebral epileptic focus, and flare skin responses were reduced by left cerebral resections in contrast with an increase after right cerebral resections. The findings demonstrate a differential role of the left and right cerebral hemispheres on immune functions in humans.

Cytokine production by spleen cells after social defeat in mice: activation of T cells and reduced inhibition by glucocorticoids.

Social disruption (SDR) is an effective model of social stress associated with an enhanced inflammatory reactivity of the immune system. The aim of the present study was to further describe SDR effects on cytokine production by spleen cells, testing selectively monocyte and T cell functions as a result of this stressor. For this purpose, splenocytes from control mice (C) and mice socially stressed for 7 days (SDR) were cultured in the presence of lipopolysaccharide (LPS) or concanavalin A (Con A). Splenocyte proliferation, cytokine production and sensitivity of spleen cells to corticosterone were assessed in vitro. The humoral response to keyhole limpet hemocyanin (KLH) immunization was assessed. SDR induced splenomegaly and enhanced splenocyte basal proliferation. The pro-inflammatory influence of SDR was confirmed by an increased release of interleukin-6 (IL-6) by LPS-stimulated cultures and by a reduced sensitivity of spleen cells to the anti-inflammatory effect of corticosterone. The mechanism increasing cytokine production in response to LPS was cytokine specific, since among inflammatory cytokines, IL-6 but not interferon-gamma (IFN-gamma) was enhanced by stress. In stressed mice, the increase in IL-6 and IFN-gamma and the decrease in IL-10 release in Con A-stimulated cultures indicate that SDR did not modify the Th1/Th2 cytokine balance but globally activated T cells. Plasma anti-KLH antibody levels were similar in both groups. Wounded and non-wounded mice presented similar responses to stress. This study shows that social disruption stress enhances the reactivity of cells from both the acquired and innate immune systems.

Chronic psychosocial stress down-regulates central cytokines mRNA.

Brain cytokines have been implicated in brain plasticity and mood alterations. We present here the first evidence of a chronic stress-induced modulation of central cytokines, in absence of experimentally induced inflammatory processes. Several brain areas were extracted from stressed and control mice and cytokines mRNA analyzed with semi-quantitative RT-PCR. Mice subjected to chronic psychosocial stress showed decreased interleukin (IL)-1beta mRNA levels in the hippocampus, decreased IL-1Receptor antagonist in the striatum and pituitary, decreased tumor necrosis factor (TNF)-alpha in the striatum and hippocampus, and decreased glucocorticoid receptor (GR) in the striatum and hippocampus compared to group housed sibling mice. An independent group of mice subjected to chronic psychosocial stress also showed increased plasma corticosterone. These findings may open new perspectives for understanding the pathophysiological basis of chronic stress-induced disorders.

Importance of fighting in the immune effects of social defeat.

Social defeat involves a clear physical component in the form of fight-induced injuries. The impact of body injuries on the immune response is not yet well known. In this study we compared the endocrine and immune responses to two types of social defeat in mice, one limiting the occurrence of skin injuries (mild social stress, MSS), and the other not (social disruption stress, SDR). In the two situations, six defeats were applied within 1 week. Plasma corticosterone and IL-6 levels were measured in blood samples taken after social defeat. Reactivity to LPS and sensitivity to corticosterone (CS) of spleen cells was assessed by measuring the in vitro production of cytokines (IL-6, IFN-gamma and IL-10) in response to LPS under a range of increasing concentrations of CS. The two types of stressors induced a similar plasma corticosterone response, but SDR mice showed significantly higher plasma IL-6 than MSS mice. Splenocytes from SDR but not from MSS mice produced more IL-6 and IL-10 in response to LPS and presented an altered responsiveness to CS in comparison to control mice. We conclude that the procedure involving fights and skin injuries was able to modulate the immune response in the spleen, whereas the procedure preventing the occurrence of fights did not. The increased immune reactivity observed in the fight-associated procedure could result from either a stronger psychological stress or a direct immune activation through the wounds.

Cytokine stress responses depend on lateralization in mice.

In mice, lateralization as assessed by paw preference represents a behavioral trait linked to immune reactivity and stress susceptibility. Right-pawed mice are more reactive to stress than left-pawed animals when brain metabolism, activation of the corticoid axis, and depression of lymphoproliferation are studied. Since stress responses include cytokine production, we address the possibility that lateralization influences the production of cytokines--especially interleukin (IL)-1--responsible for depression of lymphoproliferation and activation of the corticoid axis. Increased plasma IL-1 level that may be considered as a stress marker, was observed in right- but not in left-pawed mice submitted to a 4 h-restraint. Likewise, plasma levels were greater in right- than in left-pawed animals 2 h after the administration of a low dose of lipopolysaccharides (LPS). By contrast, there was no lateralization effect in restraint-induced plasma level of IL-6 or in the LPS-induced increase in plasma IL-10. Prazosin, an alpha1/alpha2 adrenoreceptor antagonist, drastically increased plasma IL-10 induced by LPS, reduced plasma levels of IL-1 and abolished the effect of lateralization observed after LPS alone. This suggests that alpha-adrenergic modulation of IL-1 production depends on lateralization through mechanisms that need further investigation.

Lateralization and catecholaminergic neuroimmunomodulation: prazosin, an alpha1/alpha2-adrenergic receptor antagonist, suppresses interleukin-1 and increases interleukin-10 production induced by lipopolysaccharides.

OBJECTIVE: The brain has previously been shown to asymmetrically modulate neurochemical, neuroendocrine and immune responses to lipopolysaccharides (LPS). As these responses are reversed by a chemical sympathectomy, it can be hypothesized that the asymmetry in the functioning of the sympathetic nervous system may be one of the mechanisms by which the brain hemispheres asymmetrically modulate immune reactivity. METHODS: The effects of prazosin, an alpha1/alpha2-adrenergic receptor antagonist, on the production of interleukin (IL)-1beta and IL-10 induced by LPS was studied in mice selected for their paw preference. RESULTS: Two hours after intraperitoneal injection of 5 microg of LPS, plasma levels of IL-1beta were higher in right-pawed mice as compared to left-pawed or ambidextrous animals. No lateralization effect was observed for LPS-induced plasma IL-10 levels. Prazosin, 10 mg/kg, injected intraperitoneally half an hour before LPS, reduced plasma levels of IL-1beta and abolished the effect of lateralization. By contrast, prazosin drastically increased plasma levels of IL-10 in response to LPS and the production of corticosterone in untreated controls. CONCLUSIONS: These results suggest that the catecholaminergic modulation of immune reactivity depends on lateralization. This work further demonstrates that prazosin is endowed with anti-inflammatory properties that may be considered side effects of this drug, which is widely prescribed in the treatment of hypertension.

Effects of antidepressants on cytokine production and actions.

There are intriguing analogies between many features of depression and physiological and behavioral responses to infection, which are mediated by the brain effects of cytokines. These observations suggest that depression can be considered as a psychoneuroimmunological disorder where a central increase of pro-inflammatory cytokines, may have adverse consequences on the functional activity of the neurochemical and neuroendocrine systems implicated in the symptoms of the disorder. According to this hypothesis, the therapeutic effects of antidepressants should be at least partly exerted by attenuating the brain expression and/or actions of pro-inflammatory cytokines. Despite their inherent limitations, animal models of depression that are based on behavioral and pharmacological analogies with the symptoms observed in humans, represent the best available tool to test this hypothesis and to investigate the action mechanisms of the immune effects of antidepressants. Treatment with different classes of antidepressants indeed conferred protection against cytokine-induced depressive-like biological and behavioral changes. This 'anti-inflammatory' profile may be due to alterations of the pro-/anti-inflammatory cytokine balance. The mechanisms underlying these effects of antidepressants are presently unknown, but the available literature suggests several possibilities, including actions on different molecules representing potential mediators of mood disorders induced by cytokines. The studies summarized in this review have opened up new vistas in both the pathophysiology of depression and the pharmacology of antidepressants. Whether their demonstrated immune effects are a side effect or a significant part of their clinical activity still remains to be elucidated.

Treatment of cytokine-induced depression.

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-alpha-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.

Chronic mild stress in mice decreases peripheral cytokine and increases central cytokine expression independently of IL-10 regulation of the cytokine network.

OBJECTIVES: Accumulating evidence indicates that stress leads to an increased expression of pro-inflammatory cytokines such as interleukin (IL)-6. The production and action of pro-inflammatory cytokines are down-regulated by anti-inflammatory cytokines such as IL-10. This makes IL-10-deficient mice a potentially useful model to assess the effects of stress on cytokine production. METHODS: In the present study, IL-10-deficient mice were compared to wild-type mice in their behavioural and cytokine response to a chronic mild stress procedure. RESULTS: The 3-week chronic mild stress decreased body weight gain and sucrose consumption. It also resulted in a decreased expression of peripheral IL-1beta and IL-6 and an increased expression of brain IL-6. This last change in IL-6 was correlated to body weight loss in stressed mice. However, IL-10-deficient mice did not differ from wild-type mice in their response to the chronic mild stress procedure, despite substantial differences in functioning of the cytokine network. CONCLUSION: These results are interpreted in the context of the relationship between cytokines and behaviour.