Differential interleukin-1 receptor antagonism on pancreatic beta and alpha cells. Studies in rodent and human islets and in normal rats.
The monokines interleukin-1 alpha and -beta have been implicated as effector molecules in the immune-mediated pancreatic beta-cell destruction leading to insulin-dependent diabetes mellitus. Here we investigated the effects of interleukin-1 receptor antagonism on insulin and glucagon release of rat, mouse and human islets exposed to recombinant human interleukin-1 beta, and on interleukin-1 beta induced changes in blood glucose, serum insulin and serum glucagon levels in Wistar Kyoto rats. The interleukin-1 receptor antagonist reduced the co-mitogenic effect of interleukin-1 beta on mouse and rat thymocytes with a 50% inhibitory concentration of 10- and 100-fold molar excess, respectively. Complete inhibition was obtained with a 100-1,000-fold molar excess. However, at a 100-fold molar excess the interleukin-1 receptor antagonist did not antagonise the potentiating effect of interleukin-1 beta on rat islet insulin accumulation during 3 and 6 h of exposure or of interleukin-1 beta-induced inhibition of insulin release after 24 h. In contrast, interleukin-1 beta-stimulated islet glucagon release was completely antagonised by a 100-fold molar excess of interleukin-1 receptor antagonist. A 10,000-fold molar excess of interleukin-1 receptor antagonist was needed to antagonise interleukin-1 beta stimulatory and inhibitory effects on rat beta-cell function in vitro. A 100-fold excess of interleukin-1 receptor antagonist could not counteract interleukin-1 beta effects on mouse and human beta cells, excluding species difference in the efficacy of the human interleukin-1 receptor antagonist.(ABSTRACT TRUNCATED AT 250 WORDS)
Zumsteg
U
U
Steno Diabetes Center, Gentofte, Denmark.
Reimers
J I
JI
Pociot
F
F
Mørch
L
L
Helqvist
S
S
Brendel
M
M
Alejandro
R
R
Mandrup-Poulsen
T
T
Dinarello
C A
CA
Nerup
J
J
D000818:Animals; D000906:Antibodies / Q000494:pharmacology; D002478:Cells, Cultured; D005947:Glucose / Q000494:pharmacology; D006801:Humans; D007328:Insulin / Q000378:metabolism*; D000078790:Insulin Secretion; D007375:Interleukin-1 / Q000494:pharmacology*; D007515:Islets of Langerhans / Q000187:drug effects / Q000378:metabolism*; D007700:Kinetics; D008213:Lymphocyte Activation; D008297:Male; D051379:Mice; D008809:Mice, Inbred C3H; D051381:Rats; D017208:Rats, Wistar; D017472:Receptors, Interleukin-1 / Q000037:antagonists & inhibitors*; D011994:Recombinant Proteins / Q000494:pharmacology; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology*; D013950:Thymus Gland / Q000276:immunology
D000906:Antibodies; D007328:Insulin; D007375:Interleukin-1; D017472:Receptors, Interleukin-1; D011994:Recombinant Proteins; D005947:Glucose