Circulating interleukin-10 and interleukin-12 in Parkinson's disease.
ABSTRACT Interleukin (IL)-12 is a heterodimeric cytokine produced by activated blood monocytes, macrophages and glial cells. It enhances differentiation and proliferation of T cells and increases production of proinflammatory cytokines. IL-10 is a pleiotropic cytokine produced by both lymphocytes and mononuclear phagocytes including microglia. Recent studies demonstrated the neuroprotective effect of IL-10. There is little information about the involvement of IL-12 or IL-10 in the pathophysiology of Parkinson's disease (PD).
The objective of our study was to assess the role of IL-12 as a potential marker of immune reactions in patients with PD and to investigate whether IL-10, an immunosuppressive cytokine, may have a neuroprotective effect in the pathogenesis of PD.
We measured using immunoassay serum IL-12 and IL-10 levels in 41 patients with PD in comparison with serum levels in 19 healthy subjects (controls) age and sex matched. IL-12 and IL-10 levels were tested for correlation with sex, age, disease duration, Hoehn and Yahr stage and the UPDRS III score.
The PD group presented with significantly increased IL-10 levels when compared with the control group (P = 0.02). The increase observed was not affected by the treatment status. A strong and significant correlation between IL-10 and IL-12 levels was observed in patients with PD (R(S) = 0.7, P < 0.000001).
Our findings suggest that IL-10 may be involved in the pathogenetic mechanisms of PD. The elevation of IL-10 and the significant correlation between IL-10 and IL-12, a proinflammatory cytokine, may suggest that immunological disturbances and neuroprotective mechanisms are involved in patients with PD.
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ABSTRACT: Interleukin-10 markedly reduces production of proinflammatory cytokines by activated microglia or macrophages and downregulates the expression of activating molecules on these cells. In studies performed in adults or in cell cultures, interleukin-10 protected against hypoxic-ischemic neuronal death and against lipopolysaccharide-mediated oligodendrocyte cell death. Furthermore, it was recently shown that interleukin-10 counteracts metabolic and microcirculatory effects of hypoxia-ischemia in the perinatal pig brain. Intracerebral injection of the glutamatergic analogue ibotenate to newborn mice induces cortical plate and white matter lesions mimicking the brain damage associated with cerebral palsy, and pretreatment with proinflammatory cytokines such as interleukin-1-beta or with interleukin-9 significantly exacerbates these lesions. The present study evaluated the influence of interleukin-10 on ibotenate-induced brain lesions in newborn mice under basal conditions or after exposure to cytokines. Intraperitoneal injection of interleukin-10 for 3 days following ibotenate significantly reduced the size of excitotoxic brain lesions. Intraperitoneal injection of neutralizing anti-interleukin-10 antibody for 3 days following ibotenate had no detectable effect and no difference in ibotenate-induced brain lesion size was found between wild type pups and pups deleted for the interleukin-10 gene, suggesting that endogenous interleukin-10 in newborn mice may have limited effects. Co-administration of intracerebral ibotenate and interleukin-10 had no detectable effect, arguing against a direct neuroprotective effect of interleukin-10 on neurons. While pretreatment with intraperitoneal interleukin-10 alone had no detectable effect on excitotoxic brain lesions, interleukin-10 given with interleukin-1-beta pretreatment blunted the toxic effects of interleukin-1-beta. On the other hand, combined pretreatment with IL-9 and anti-IL-10 antibody largely reversed the exacerbating effect of IL-9 on excitotoxic brain lesions. Altogether, these data suggest that, in newborn mice, exogenous interleukin-10 can be neuroprotective when acting in an inflammatory context.Developmental Brain Research 04/2003; 141(1-2):25-32. · 1.78 Impact Factor
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ABSTRACT: Perinatal brain injuries and the subsequent development of cerebral palsy are closely associated with intrauterine infections and inflammatory response. Antibiotics have proven futile in reducing perinatal brain injuries. We tested whether treatment with the anti-inflammatory cytokine IL-10 could have beneficial effects during a concomitant endotoxin and cerebral hypoxic-ischemic challenge. Thirty-three newborn piglets were randomized to pretreatment with: Controls: placebo, Endotoxin: 2 kU/kg bolus and infusion of 1 kU/kg per h of endotoxin, or Endotoxin+IL-10: endotoxin in addition to 50 microg/kg of porcine recombinant IL-10. We induced cerebral hypoxia-ischemia by bilateral clamping of the common carotid arteries and ventilation with 8% oxygen for 20 min followed by 3 h of reoxygenation/reperfusion. Extracellular lactate, pyruvate, glycerol and glutamate, microcirculation and tissue oxygenation were monitored in the striatum by microdialysis, laser Doppler flow and oxygen tension probe, respectively. During and/or after cerebral hypoxia-ischemia, Endotoxin caused marked deterioration of the cerebral metabolic situation with higher lactate/pyruvate ratio (P=0.003), compared to Controls and Endotoxin+IL-10. This was caused mainly by very low levels of pyruvate (P=0.001). During the following reoxygenation, Endotoxin compromised cerebral microcirculation (P=0.038) and tissue oxygenation (P=0.012) compared to Controls and Endotoxin+IL-10. After a period of remission, a secondary energy failure and a new rise in the lactate/pyruvate ratio was seen in Endotoxin (P=0.002), but not in Controls or Endotoxin+IL-10. At the end of observation, only the Endotoxin+IL-10 group had regained their baseline values in all variables. Thus IL-10 counteracts acute effects of endotoxin on cerebral metabolism, microcirculation and oxygen tension during hypoxia-ischemia in the perinatal brain.Brain Research 07/2002; 942(1-2):87-94. · 2.88 Impact Factor
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ABSTRACT: A hallmark of the immunopathology associated with Alzheimer's disease (AD) is the presence of activated microglia surrounding senile plaque deposits of beta-amyloid (A beta) peptides. A beta peptides have been shown to be potent activators of microglia and macrophages, but little is known about endogenous factors that may modulate their responses to amyloid. We investigated whether the 'anti-inflammatory' cytokines IL-4, IL-10 and IL-13 could regulate A beta-induced production of the inflammatory cytokines IL-1 alpha, IL-1 beta, TNF-alpha, IL-6 and the chemokine MCP-1. A beta(1-42) time- and dose-dependently induced the production and secretion of these inflammatory proteins in the human THP-1 monocyte cell line and in primary murine microglia, similar to what was observed for lipopolysaccharide (LPS) stimulated cells. IL-10 was found to suppress all A beta and LPS-induced inflammatory proteins measured (IL-1 alpha, IL-1 beta, IL-6, TNF-alpha and MCP-1) in both cell types with the exception of LPS-induced MCP-1 in THP-1 cells where no change was observed. In contrast to the inhibition observed for IL-10, both IL-4 and IL-13 enhanced MCP-1 secretion. IL-4 and IL-13 reduced IL-6 secretion, but effects on IL-1 alpha, IL-1 beta or TNF-alpha were dependent on cell type and stimulus conditions. Additional experiments using RT-PCR showed that IL-4, IL-10 and IL-13 mRNA is found to be present in human brain tissue. These results show that IL-4, IL-10, and IL-13 differentially regulate microglial responses to A beta and may play a role in the inflammation pathology observed surrounding senile plaques.Journal of Neuroimmunology 03/2001; 113(1):49-62. · 3.03 Impact Factor