NeuroImmunoModulation

<i>Objectives:</i> The DNA-binding activity of nuclear factor ĸB (NFĸB) is elevated in brain of aged mice, resulting in elevated levels of the inflammatory cytokine interleukin (IL)-6. The purpose of this study was to determine if in the brain of aged mice a decrease in the anti-inflammatory cytokine IL-10 contributes to the increase in IL-6. <i>Methods:</i> In initial studies coronal brain sections and glial cells from adult (6-months-old) and aged (24-months-old) mice were incubated in the presence or absence of lipopolysaccharide (LPS) and the concentrations of IL-6 and IL-10 in supernatants were determined. In subsequent studies, the effect of recombinant murine IL-10 on constitutive and inducible NFĸB activity, IL-6 mRNA expression and IL-6 protein secretion by glia cultured from brains of adult and aged mice was determined. <i>Results:</i> Coronal brain sections and glia from aged mice secreted more IL-6 and less IL-10 than brain sections and glia from adults. This effect of age was evident in the absence and presence of LPS and suggested that a decrease in IL-10 production permitted increased IL-6 production. Consistent with this idea, treatment of glia from aged mice with recombinant IL-10 decreased both constitutive and inducible binding of NFĸB to the IL-6 gene promoter. The decrease in NFĸB activity was associated with a reduction of IL-6 mRNA and protein. Exogenous IL-10, however, had no effect on NFĸB activity, which was undetectable in unstimulated glia from adult mice, and did not decrease steady-state levels of IL-6 mRNA or IL-6 protein secretion. <i>Conclusions:</i> Collectively, these studies suggest that IL-10 constrained IL-6 gene expression in the adult brain, but in the aged brain it decreased and thus enabled a cascade of intracellular events that increased expression of the IL-6 gene.

Increasing evidence indicates that factors such as oxidative stress, plasma homocysteine increase and glutathione depletion, elevated pro-inflammatory cytokines and advanced glycation end products can play a role in Alzheimer’s disease (AD) pathogenesis. The receptor for advanced glycation end products (RAGE) is a cell surface receptor that has been implicated in neurodegeneration, and a soluble isoform of RAGE (sRAGE) has the ability to prevent the adverse effects of RAGE signaling by acting as a decoy. Twenty-five patients with AD, 26 with mild cognitive impairment (MCI) and 44 age-matched control subjects were studied. All subjects were classified according to their clinical, cognitive and positron emission tomography study. Serum levels of sRAGE and TNF-α receptor II were not significantly different in AD or MCI patients compared to controls. Total plasma levels of glutathione and its metabolite cysteinglycine were decreased in AD and MCI patients compared to the control group. In addition, AD patients presented significantly increased plasma homocysteine compared to those in MCI patients and controls. We found significant positive correlations between sRAGE and glutathione, cysteinglycine and cysteine levels. Moreover, a significant negative correlation between the total score of cognitive impairment and homocysteine levels, and significant positive correlations with glutathione, cysteinglycine and cysteine levels were observed. These findings indicate that plasma aminothiol compounds are associated with AD and MCI patients and with their cognitive status.

<i>Background:</i> Chronic stress has been associated with detrimental or maladaptive neuroendocrine and immunological changes. <i>Objectives:</i> We assessed the neuroendocrine and immunological correlates of a realistic chronic stress experienced by strictly healthy caregivers of Alzheimer’s disease patients and age-matched controls. <i>Methods:</i> We screened 330 caregivers and 206 non-caregivers according to the ‘strictly healthy’ conditions established by the SENIEUR protocol. Forty-one strictly healthy caregivers (60.56 ± 16.56 years) and 33 non-stressed controls (60.27 ± 14.11 years) were selected for this study. Salivary cortisol and dehydroepiandrosterone sulfate (DHEAS) were assessed at multiple points by radioimmunoassay. Peripheral T cell proliferation and cellular sensitivity to glucocorticoids (corticosterone and dexamethasone, DEX) were evaluated by colorimetric assays. We also examined the hypothalamic-pituitary-adrenal (HPA) axis response to the administration of a low-dose DEX in vivo. <i>Results:</i> The caregivers were significantly more stressed, anxious and depressed than non-caregivers (all p < 0.0001), in contrast to similar cortisol levels. Caregivers had reduced DHEAS levels (–32%, p < 0.0001), an increased cortisol/DHEAS ratio (39.7%, p < 0.0001) and impaired HPA axis response to DEX intake. Caregivers had a higher T cell proliferation (p < 0.0001) and increased sensitivity to glucocorticoids in vitro (p < 0.01) as compared to non-stressed controls. <i>Conclusions:</i> Our results suggest that the maintenance of health in chronically stressed populations may be associated with both protective and detrimental neuroendocrine and immunological changes.

<i>Objectives:</i> Major depression is associated with increased circulating interleukin-2 (IL-2) levels, and IL-2 immunotherapy may provoke depressive symptoms, leading to the suggestion that this cytokine may contribute to the evolution of affective disorders. Although depression is a relatively chronic condition, and immunotherapy involves repeated cytokine administration, animal studies have typically assessed the consequences of acute cytokine treatment. The present investigation assessed several behavioral and neurochemical effects of chronic IL-2 infusion. <i>Methods:</i> Behaviors reflecting anhedonia and/or anorexia, sickness behavior, plasma corticosterone and norepinephrine (NE) activity in the paraventricular nucleus (PVN) of the hypothalamus were assessed following continuous infusion of IL-2 over 7 days in CD-1 mice. <i>Results:</i> The cytokine treatment reduced the consumption of a highly favored palatable substance (chocolate milk) and reduced locomotor activity monitored over the course of the 7-day period. Although sickness behaviors were also increased significantly by the treatment, the degree of sickness behavior was actually modest. While a chronic, variable stressor also affected consumption of the palatable food, this treatment did not enhance the effects of IL-2. Furthermore, in contrast to acute and chronic stressors that increased plasma corticosterone levels and the utilization of NE within the PVN of the hypothalamus, IL-2 did not promote such effects and did not modify the impact of the stressors. <i>Conclusion:</i> While IL-2 may induce anorexia or anhedonia, the effects of this treatment are distinguishable from those elicited by stressors and those typically elicited by proinflammatory cytokines. The data are related to findings suggesting a link between IL-2 and depressive illness.

Human T cell lymphotropic virus type 1 (HTLV-1) is the causal agent of HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP). While the immune response to HTLV-1 infection is polarized to the Th1-type, chronic helminth infections drive the Th2- and T regulatory-type, and are able to downregulate the inflammatory response in some autoimmune diseases. <b><i>Objective:</i></b> To evaluate whether <i>Schistosoma </i>spp. antigens alter the in vitro cytokine response in HTLV-1 infection. <b><i>Methods:</i></b> The recombinant <i>Schistosoma</i> antigens Sm29 and ShTSP2 (tetraspanin) and PIII, a fraction of <i>the Schistosoma mansoni</i> adult worm antigen were added to peripheral blood mononuclear cell (PBMC) cultures of HTLV-1-infected individuals and the levels of interferon (IFN)-&#947; and interleukin (IL)-10 in the supernatants were measured using the ELISA sandwich technique. <b><i>Results:</i></b> Compared to the levels of cytokine in nonstimulated cultures, the levels of IFN-&#947; were reduced in 50, 47 and 50% of patients by the presence of Sm29, ShTsp2 and PIII, respectively. The downregulation of IFN-&#947; production in the presence of Sm29 antigen was observed mainly in subjects who had lower basal levels of this cytokine. The levels of IL-10, however, increased by the addition of the three antigens in the cultures in 74, 62 and 44% of individuals, respectively. In addition, there was a decrease in the ratio of IFN-&#947;/IL-10 levels in cultures stimulated with Sm29 and ShTSP2 when compared to nonstimulated ones. <b><i>Conclusions:</i></b> The <i>Schistosoma </i>spp. antigens used in this study were able to downmodulate IFN-&#947; production in vitro in HTLV-1 infection. This may be associated with the increased levels of IL-10 induced by the antigens.

<i>Background and Aim:</i> The dual action of microglia in neurodegenerating diseases has been controversial for some time. Recent studies indicate that microglia senescence might be the key determinant. When microglia age, they function abnormally and fail to respond correctly to stimuli, which eventually promotes neurodegeneration. Accumulating evidence has shown a close relationship between inflammation and aging. Since neuroinflammation is characterized by microglia activation, we assessed if the repeated activation of microglia would lead to senescence. <i>Method:</i> The microglia cell line BV2 was repeatedly stimulated every 48 h with lipopolysaccharide (LPS; 10 ng/ml) and senescence was evaluated by β-galactosidase staining and the presence of senescence-associated heterochromatic foci as well as by cell cycle arrest detection by flow cytometry. The senescence-associated protein p53 was also detected by Western blot. <i>Results:</i> β-Galactosidase staining was barely detectable in control cells, while it tended to increase with repeated LPS stimulation and was positive in most cells after stimulation with LPS 6 times. Similarly, senescence-associated heterochromatic foci were most prominent in cells repeatedly stimulated with LPS, while almost undetectable in control cells or cells receiving a single stimulation. p53 expression was highest in the cells that received LPS stimulation 6 times, and the largest number of cells arrested in the G0/G1 phase was observed in this same group. <i>Conclusion:</i> Microglial cells tend to undergo senescence after repeated activation, implying that microglia senescence may start after multiple inflammatory challenges.

Lipopolysaccharide (LPS)- and concanavalin A (ConA)-induced proliferation and T lymphocyte subsets were measured in spleen and submaxillary lymph nodes of male rats injected with cyclosporine (5 mg/kg s.c. for 5 days, at 12.00 or 24.00 h; animals kept under light from 08.00 to 20.00 h daily). One hour before the third injection, Freund’s complete adjuvant or its vehicle was administered. A suppressive effect of cyclosporine on the mitogenic action of LPS was seen in the spleen of rats injected with cyclosporine at noon whereas the effect of ConA remained unaffected. CD4+, CD8+ and CD4+-CD8+ cells decreased in spleen and lymph nodes of Freund’s adjuvant-injected rats only with cyclosporine given at noon. The results further support occurrence of time-of-day-dependent effects of cyclosporine on lymphocyte subsets and proliferation.

Wallerian degeneration, the self-destructive set of cellular and molecular processes by which degenerating axons and myelin are cleared after injury, is initiated by macrophages and Schwann cells. Molecular inflammatory mediators such as cytokines (IL-1, IL-6, IL-10, and TNF-α, among others), transcription factors (NF-ĸB, c-Jun), the complement system and arachidonic acid metabolites have been shown to modulate these processes in various studies. However, the exact role that each of these mediators plays during axonal degeneration and regeneration has not been fully established. Understanding the molecular basis of these interactions between the immune system and peripheral nerve injury would open the possibility of targeting these inflammatory mediators as therapeutic interventions. In this review we attempt to integrate the current evidence generated around this issue, and to explore the therapeutic possibilities that arise.