LINOMIDE INCREASES PLASMA-CORTICOSTERONE IN NORMAL RATS, BUT DOES NOTPREVENT THE INHIBITORY-ACTION OF IL-1 ON BETA-CELLS IN-VIVO OR EX-VIVO

Recently, the synthetic immunomodulator Linomide (quinoline-3-carboxam ide, LS 2616) was reported to prevent IDDM and insulitis in NOD mice. The mechanism for this protective effect is not known. The cytokine in terleukin 1 (IL-1) may be a pathogenetic factor in the initial destruc tion of the beta-cells leading to IDDM. This study was undertaken to i nvestigate the influence of Linomide on IL-1 beta induced diabetogenic and hormonal changes in the rat in vivo, and on IL-1 beta mediated sy nthesis of NO and inhibition of insulin secretion in isolated islets o f Langerhans ex vivo. Normal male Wistar Kyoto rats received 4.0 mu g/ kg of recombinant human IL-1 beta (rhIL-1 beta) i.p. daily for 5 days with or without Linomide (8-9 mg/kg/day) in the drinking water. Litter s of neonatal Wistar rats were pretreated for 3 days with injections o f 10 mg/kg of Linomide i.p., and pancreatic islets of Langerhans were isolated for ex vivo studies, Linomide alone caused significant hyperc orticosteronemia, hypoglucagonemia, lymphopenia and neutrophilia, Lino mide had no effect on IL-1 beta induced hyperglycemia, hyperglucagonem ia, lymphopenia, neutrocytosis, or hypercorticosteronemia on day three and hypocorticosteronemia on day five. Further, Linomide did not prev ent rhIL-1 beta mediated reduction in insulin secretion or increase in NO synthesis ex vivo. In conclusion, Linomide does not seem to exert its protective effect on IDDM development via inhibition of interleuki n 1 action on islet insulin release or NO production, but the increase in plasma corticosterone may contribute to the understanding of the i mmunomodulatory effects of Linomide.