REGULATION OF INTERLEUKIN-6 (IL-6)

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Work on this project was completed and phased out during the past year. The goal of the work was to elucidate the mechanism whereby prostaglandin E2 (PGE2) regulates IL-6 and IL-10 production. PGE2 is a potent immunomodulator and is known to regulate production of a wide array of cytokines. IL-6 and IL-10 are generally upregulated by PGE2 whereas TNF-alpha is down-regulated. We found that PGE2 could augment the levels of both IL-6 and IL-10 produced by murine peritoneal macrophages but the molecular pathways that led to their augmentation differed. Also, the time of exposure of the macrophages to PGE2 relative to addition of an inflammatory stimulus significantly altered the levels of cytokines produced. Pre-treatment of the macrophages with PGE2 resulted in diminished IL-6 production following macrophage activation but this resulted from the fact that IL-10 levels had been augmented; IL-10 is a potent inhibitor of IL-6 synthesis. In the absence of IL-10, PGE2 augmented IL-6 synthesis regardless of whether it was added prior to or after the inflammatory stimulus. Subsequent experiments investigated the molecular pathway leading to increased macrophage IL-6 and IL-10 production after exposure to PGE2. Synthesis of IL-10 in response to exogenous PGE2 was dependent upon activation of the p38 MAP kinase whereas synthesis of IL-6 was not. This was documented using inhibitors which are selective for p38 kinase catalytic activity and looking at both RNA and protein synthesis for both cytokines. p38 kinase inhibitors were able to inhibit IL-6 production in activated macrophages but this occurred primarily as an indirect result of their concurrent inhibition of cyclooxygenase-2 expression and endogenous PGE2 synthesis. The results indicated that macrophage IL-10 and IL-6 expression are differentially regulated by p38 MAP kinase. The results of these studies are currently under revision for publication in a peer-reviewed journal.