Linomide increases plasma corticosterone in normal rats, but does not prevent the inhibitory action of IL-1 on beta-cells in vivo or ex vivo.
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 beta-cells leading to IDDM. This study was undertaken to investigate the influence of Linomide on IL-1beta induced diabetogenic and hormonal changes in the rat in vivo, and on IL-1beta mediated synthesis of NO and inhibition of insulin secretion in isolated islets of Langerhans ex vivo. Normal male Wistar Kyoto rats received 4.0 microg/kg of recombinant human IL-1beta (rhIL-1beta) 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-1beta induced hyperglycemia, hyperglucagonemia, lymphopenia, neutrocytosis, or hypercorticosteronemia on day three and hypocorticosteronemia on day five. Further, Linomide did not prevent rhIL-1beta 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.
Steno Diabetes Center, Gentofte, Denmark.
U B
UB
Christensen
D
D
Mauricio
J I
JI
Reimers
H U
HU
Andersen
T
T
Kalland
J
J
Nerup
T
T
Mandrup-Poulsen
D000276:Adjuvants, Immunologic / Q000494:pharmacology*; D000818:Animals; D001772:Blood Cell Count / Q000187:drug effects; D003345:Corticosterone / Q000097:blood*; D005934:Glucagon / Q000037:antagonists & inhibitors; D006801:Humans; D006912:Hydroxyquinolines / Q000494:pharmacology*; D007329:Insulin Antagonists; D007375:Interleukin-1 / Q000037:antagonists & inhibitors* / Q000633:toxicity*; D007515:Islets of Langerhans / Q000187:drug effects*; D008297:Male; D011897:Random Allocation; D051381:Rats; D011921:Rats, Inbred WKY
D000276:Adjuvants, Immunologic; D006912:Hydroxyquinolines; D007329:Insulin Antagonists; D007375:Interleukin-1; C045282:roquinimex; D005934:Glucagon; D003345:Corticosterone