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.
Dayer-Métroz
M D
MD
Institute of Clinical Biochemistry, Centre médical universitaire, Geneva, Switzerland.
Wollheim
C B
CB
Seckinger
P
P
Dayer
J M
JM
D000818:Animals; D015232:Dinoprostone / Q000096:biosynthesis; D006801:Humans; D007213:Indomethacin / Q000494:pharmacology; D007328:Insulin / Q000096:biosynthesis*; D053590:Interleukin 1 Receptor Antagonist Protein; D007375:Interleukin-1 / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D007515:Islets of Langerhans / Q000187:drug effects* / Q000378:metabolism; D009924:Organ Culture Techniques; D051381:Rats; D011919:Rats, Inbred Strains; D011971:Receptors, Immunologic / Q000187:drug effects; D017472:Receptors, Interleukin-1; D011994:Recombinant Proteins / Q000494:pharmacology; D012795:Sialoglycoproteins / Q000494:pharmacology*
C507763:IL1RN protein, human; D007328:Insulin; D053590:Interleukin 1 Receptor Antagonist Protein; D007375:Interleukin-1; D011971:Receptors, Immunologic; D017472:Receptors, Interleukin-1; D011994:Recombinant Proteins; D012795:Sialoglycoproteins; D015232:Dinoprostone; D007213:Indomethacin