115 : Interleukin-10 dependent alterations in the hypothalamic–pituitary–adrenal axis and behavior during inflammatory arthritis

Abstract

In addition to its widely recognized role as an anti-inflammatory cytokine, interleukin (IL)-10 is emerging as a potential regulator of the hypothalamic–pituitary–adrenal (HPA) axis, a major part of the neuroendocrine system that controls reaction to stress. The HPA axis is a homeostatic feedback process that produces glucocorticosteroids and hormones that govern digestion, mood and certain immune responses. In rheumatoid arthritis (RA), appropriate control of the HPA axis is often lost and contributes to the incidence of fatigue and depression in patients. In parallel, both RA and depression have been linked to abnormal IL-10 production. In IL-10 deficient (IL-10KO) mice, the inflammatory histopathology associated with antigen-induced arthritis (AIA) is enhanced compared to wild-type (WT) controls. However, little is known about the interplay between the immune and neuroendocrine systems during inflammatory arthritis. Here, we consider IL-10 production in neuroendocrine tissues as a potential mediator of HPA axis function and behavior during arthritis. IL-10KO and WT mice were examined by open field test (OFT) to assess locomotor and exploratory activity following AIA onset. HPA tissue samples, assessed for alterations in gene expression, were harvested at Day 3 and Day 28 of AIA. Compared to WT, IL-10KO mice showed elevated adrenal adrenocorticotropic hormone receptor and pituitary pro-opiomelanocortin expression at Day 3. Coinciding with these HPA axis abnormalities, IL-10KO mice displayed reduced locomotor activity, and spent less time exploring the center of the arena (index of anxious-like behavior). While OFT behaviors in both genotypes returned to baseline by Day 7, joint degeneration progressed. At Day 28, severe joint histopathology was concurrent with elevated hypothalamic glucocorticoid receptor and melatonin receptor 1a expression in IL-10KO mice. These data indicate that the induction of disease coincides with fluctuations in the control of the HPA axis and emphasize a regulatory role for the inflammatory cytokine IL-10 during inflammatory arthritis.