Linomide Increases Plasma Corticosterone in Normal Rats, but does not Prevent the Inhibitory Action of IL-1 on β-Cells in Vivo or ex Vivo

Abstract

Recently, the synthetic immunomodulator Linomide (quinoline-3-carboxamide, LS 2616) was reported to prevent IDDM and insulitis in NOD mice. The mechanism for this protective effect is not known. The cytokine interleukin 1 (IL-1) may be a pathogenetic factor in the initial destruction of the β-cells leading to IDDM. This study was undertaken to investigate the influence of Linomide on IL-1β induced diabetogenic and hormonal changes in the rat in vivo, and on IL-1β mediated synthesis of NO and inhibition of insulin secretion in isolated islets of Langerhans ex vivo.

Normal male Wistar Kyoto rats received 4.0 μg/kg of recombinant human IL-1β (rhIL-1β) i.p. daily for 5 days with or without Linomide (8-9 mg/kg/day) in the drinking water. Litters of neonatal Wistar rats were pretreated for 3 days with injections of 10 mg/kg of Linomide i.p., and pancreatic islets of Langerhans were isolated for ex vivo studies. Linomide alone caused significant hypercorticosteronemia, hypoglucagonemia, lymphopenia and neutrophilia. Linomide had no effect on IL-1β induced hyperglycemia, hyperglucagonemia, lymphopenia, neutrocytosis, or hypercorticosteronemia on day three and hypocorticosteronemia on day five. Further, Linomide did not prevent rhIL-1β 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 interleukin 1 action on islet insulin release or NO production, but the increase in plasma corticosterone may contribute to the understanding of the immunomodulatory effects of Linomide.

Key Words:

• IDDM
• Roquinimex
• cytokines
• immunomodulation
• islets of Langerhans
• autoimmunity