Interleukin-10 (IL-10) is a cytokine, which has a wide range of activities in the immune system. Neuroendocrine cells produce IL-10 and its receptor and expression is seen in the central nervous system as well, particularly during immune-related diseases. Little is known however, about IL-10's action in regulating hypothalamic-pituitary-adrenal (HPA) interactions. In vitro and in vivo evidence suggest that IL-10 is likely an endogenous regulator in the HPA axis. In vitro IL-10 acts like corticotropin releasing factor (CRF) to induce corticotropin (ACTH) production from pituitary cells. From hypothalamic cells, IL-10 induces the release of CRF. In vivo adrenal glucocorticosteroids (GCS) appear to be regulated by IL-10 normally and in response to stress. We hypothesize that IL-10 contributes to the homeostatic regulation of the HPA axis. This may occur through direct action on HPA axis tissues as well as indirectly through the inhibition of other cytokines or hormones.
Our specific aims are as follows: 1) We will determine the differential expression and/ or regulation of IL-10 and its receptor in the HPA axis; 2) Linkage of regulation and the site of production with function will be determined by identifying the intracellular signal transduction pathways that IL-10 activates in cells of the HPA axis; 3) At the intercellular level, we will determine if IL-10 modulation of the HPA axis occurs through direct action on GCS availability and glucocorticoid receptor (GR); 4) At the whole animal level, we will determine the role of IL-10 in HPA responses during immune and physiologic stress. These studies will be accomplished in vitro using primary cells and tissue culture. In vivo studies will utilize normal and IL-10-deficient mice. Histological, molecular biological, and immunologically based techniques will be used. Results from this project should advance our understanding of how the HPA axis is regulated by IL-10 in particular and cytokines in general. These studies may lead to the identification of new molecules and mechanisms that mediate normal and pathological processes associated with stress and the HPA axis, such as Cushing's Disease, or other related diseases that have an immune component.
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