Inflammatory cytokines are commonly elevated in acute depression and are associated with resistance to monoaminergic treatment. To examine the potential role of cytokines in the pathogenesis and treatment of depression, we carried out a systematic review and meta-analysis of antidepressant activity of anti-cytokine treatment using clinical trials of chronic inflammatory conditions where depressive symptoms were measured as a secondary outcome. Systematic search of the PubMed, EMBASE, PsycINFO and Cochrane databases, search of reference lists and conference abstracts, followed by study selection process yielded 20 clinical trials. Random effect meta-analysis of seven randomised controlled trials (RCTs) involving 2370 participants showed a significant antidepressant effect of anti-cytokine treatment compared with placebo (standardised mean difference (SMD)=0.40, 95% confidence interval (CI), 0.22-0.59). Anti-tumour necrosis factor drugs were most commonly studied (five RCTs); SMD=0.33 (95% CI; 0.06-0.60). Separate meta-analyses of two RCTs of adjunctive treatment with anti-cytokine therapy and eight non-randomised and/or non-placebo studies yielded similar small-to-medium effect estimates favouring anti-cytokine therapy; SMD=0.19 (95% CI, 0.00-0.37) and 0.51 (95% CI, 0.34-0.67), respectively. Adalimumab, etanercept, infliximab and tocilizumab all showed statistically significant improvements in depressive symptoms. Meta-regression exploring predictors of response found that the antidepressant effect was associated with baseline symptom severity (P=0.018) but not with improvement in primary physical illness, sex, age or study duration. The findings indicate a potentially causal role for cytokines in depression and that cytokine modulators may be novel drugs for depression in chronically inflamed subjects. The field now requires RCTs of cytokine modulators using depression as the primary outcome in subjects with high inflammation who are free of other physical illnesses.

To test the possible role of cholecystokinin (CCK) in the decrease of social exploration induced by intraperitoneal (IP) injection of lipopolysaccharide (LPS, 100 microg/kg), mice were pretreated with IP or intracerebroventricular (ICV) injection of the CCKA receptor antagonist L-364,718 (3 mg/kg and 10 microg/kg, respectively) and the CCKB receptor antagonist L-365,260 (1 mg/kg and 10 microg/kg, respectively). L-364,718 and L-365,260 did not alter LPS-induced decrease in social investigation, whatever the route of administration, suggesting that endogenous cholecystokinin does not mediate the effect of proinflammatory cytokines on social exploration in mice.

The number of older adults with HIV-1 disease is increasing but little is known about how age influences behavioral deficits associated with HIV-1 infection. The purpose of this study was to determine in a murine model if aging influenced sickness behavior following central injection of HIV-1 gp120. In initial studies, behavioral deficits induced by acute and repeated intracerebroventricular (ICV) injection of gp120 were greater in aged mice than in adults. Furthermore, repeated ICV injection of gp120 increased hippocampal levels of IL-1 beta and IL-6 mRNA in aged mice but not in adults. To determine if IL-6, which is elevated in aged brain, affects expression of the gp120-binding target, CCR5, microglia (BV-2 cell line) were incubated with increasing concentrations of IL-6. Cell surface expression of CCR5 was increased by IL-6 in a dose-dependent manner. Additionally, IL-6 increased gp120-dependent chemotaxis. These results suggest that aging increases the sensitivity of mice to behavioral deficits caused by ICV gp120, perhaps by increasing expression of CCR5 and augmenting production of cytokines.

Inter-individual differences in brain-immune interactions have been demonstrated previously in mice using lateralization as a behavioral trait of population heterogeneity. Lipopolysaccharide (LPS), which is known to induce neurochemical, neuroendocrine, and immune responses depending on lateralization, is also able to induce sickness behavior, via the production of interleukin-1 (IL-1). The objective of this study was to determine whether lateralization can influence the behavioral response to LPS and to IL-1. To test this hypothesis, adult female C3H mice, previously selected for paw preference in a food reaching task, were injected intraperitoneally (i.p.) with 0.75 microg LPS or 0.75 microg recombinant IL-1beta. Sickness induced by these molecules was measured by depressed social behavior, increased immobility, loss of body weight, and reduced food intake during the 6 h following injection. LPS-induced sickness was similar in right- and left-pawed mice. In contrast, IL-1-induced sickness behavior was dependent on behavioral lateralization. IL-1-induced depression of social investigation was more pronounced in right-pawed mice than in left-pawed animals. Likewise, IL-1-induced immobility was more important in right-pawed mice. There was a similar trend for food intake to be lower and loss of body weight to be higher in right-pawed mice than in left-pawed animals. These results demonstrate that right-pawed mice are more sensitive to IL-1-induced sickness than left-pawed animals. They extend our previous data showing a greater susceptibility to stress of right-pawed animals. The existence of inter-individual differences in the reactivity to stress or immune activation may be useful to study the mechanisms of the various strategies used by an individual in response to environmental aggressions.

The endogenous interleukin-1 receptor antagonist is the natural inhibitor of the biological effects of interleukin-1 during inflammation. Interleukin-1 receptor antagonist refers to three isoforms: one secreted and two intracellular forms (types I and II). The objective of the present study was to investigate the expression of interleukin-1 receptor antagonist isoforms in the rat brain in vivo in response to an i.p. injection of lipopolysaccharide. The interleukin-1 receptor antagonist was studied at the messenger and protein levels by reverse transcription-polymerase chain reaction and western blot analysis, respectively. Interleukin-1 receptor antagonist messenger RNA was constitutively expressed in the brain and its expression increased in response to lipopolysaccharide. The three interleukin-1 receptor antagonist protein isoforms were up-regulated after lipopolysaccharide treatment in a time-dependent manner. Their relative expression differed according to the isoform and brain region studied. Double immunofluorescence staining revealed interleukin-1 receptor antagonist positive neurons and microglia in hippocampus 24h after lipopolysaccharide stimulation. These results demonstrate for the first time that brain cells are able to produce interleukin-1 receptor antagonist isoforms in response to a peripheral immune challenge with a predominance of the secreted over intracellular forms.