Philippe Lucien Seckinger

A natural interleukin 1 (IL-1) inhibitor counteracts the inhibitory effect of IL-1 on insulin production in cultured rat pancreatic islets.

Several lines of evidence suggest that autoimmune processes are involved in the pathogenesis of Type I diabetes mellitus. Monocyte-macrophages are among the first mononuclear cells to invade the islets of Langerhans in various murine diabetic syndromes, and blockade of monocyte-macrophage functions by injection of silica particles in these animals prevents the development of the disease. Monokines such as interleukin 1 (IL-1) are known to mediate tissue lesions by inducing collagenase and prostaglandin E2 (PGE2) production. In addition, IL-1 has been demonstrated to inhibit proinsulin biosynthesis and secretion in pancreatic islet cells. Using 3-d cultured rat islets we have found that (a) the lowering of insulin release induced by human recombinant IL-1 (rIL-1) is dose-dependent with a decrease to 21% of control value at the higher rIL-1 tested concentration (500 pg/ml), and about two times more pronounced than the decrease in cellular insulin content, which reached 44% of control value at the highest rIL-1 concentration; (b) rIL-1 stimulates islets to secrete PGE2 but the addition of indomethacin, which blocks PGE2 production, does not affect the decrease in insulin release and content caused by IL-1, suggesting a limited role of endogenous PGE2 as a mediator in this system; and (c) a specific, noncytotoxic IL-1 inhibitor, shown in other cell systems to block the binding of IL-1 to its receptor, prevents the rIL-1 lowering of insulin content and minimizes the decrease of insulin release.

An Interleukin 1 Inhibitor Affects both Cell-Associated Interleukin 1-Induced T Cell Proliferation and PGE2/Collagenase Production by Human Dermal Fibroblasts and Synovial Cells

Lipopolysaccharide (LPS) induces cell-associated interleukin 1 (IL 1) production in the human promonocytic cell line U937. Demonstration of cell-associated IL 1 activity was based on the ability of LPS-treated U937 cells, subsequently fixed with paraformaldehyde, to stimulate thymocyte proliferation in the presence of phytohemagglutinin. Like soluble IL 1 (sIL 1), cell-associated IL 1 is capable of inducing PGE2 and/or collagenase production by dermal fibroblasts and human synovial cells in a dose-dependent manner. It is thus a mediator of the inflammatory response owing to a direct intercellular contact located at the membrane level, where bound molecules may trigger inflammation at a local site of action. We reported that the natural (approximately 23 kDa) IL 1 inhibitor (IL 1 INH) from the urine of febrile patients inhibited all the sIL-1-induced biologic activities under investigation and that it acted by binding to the IL 1 receptor, thus blocking the interaction of the monokine with the receptor. Data demonstrate that the IL 1 INH also blocks cell-associated IL 1-induced T cell proliferation and PGE2 production by both dermal fibroblasts and synovial cells as well as collagenase production by the latter cell type. Thus, as for the sIL 1, a feedback mechanism exists for cell-associated IL 1-induced bioactivities.