Interleukin-1[beta] inhibits phospholipase c and insulin secretion
at sites apart from the k+ (atp) channel.
Vadakekalam, Jacob, Mary E. Rabaglia, and Stewart A. Metz.
Section of Endocrinology and the Medical Service, Middleton VA
Medical Center, Madison, Wisconsin 53705 and the Division of
Endocrinology and Metabolism and Department of Medicine, University
of Wisconsin-Madison, Madison, Wisconsin 53792
APStracts 4:0156E, 1997.
Although interleukin-1[beta] (IL-1[beta]) reduces pancreatic islet
content of ATP and GTP, the distal events which mediate its
inhibitory effects on insulin secretion remain poorly understood.
Herein, the activation of phospholipase C (PLC) was quantified during
islet perifusions. An 18 hr exposure to IL-1[beta] (100 pM) totally
vitiated activation of phospholipase C induced by glucose, an effect
which requires ATP and GTP and closure of the K+(ATP) channel.
Surprisingly, however, when islets were depolarized directly using
either of two agonists, glyburide (which does not act via generation
of purine nucleotides) or by 40mM K+ (which acts distal to the ATP
-dependent K+ channel), PLC and insulin secretion were again
obliterated by IL-1[beta]. IL-1[beta] also reduced the labeling of
phosphoinositide substrates; however, this effect was insufficient to
explain the inhibition of PLC, since the effects on substrate
labeling, but not on PLC, were prevented by co-provision of guanosine
or adenosine. Furthermore, when IL-1[beta]-treated islets were
exposed to 100 [mu]M carbachol (which activates PLC partially
independent of extracellular Ca2+), the effects were still
obliterated by IL-1[beta]. These data (together with the finding that
IL-1[beta] inhibited Ca2+-induced insulin release) suggest that, in
addition to its effects on ATP synthesis and thereby on the K+(ATP)
channel, IL-1[beta] has at least two undescribed, distal effects to
block both PLC as well as Ca2+-induced exocytosis. The latter
correlated best with IL-1[beta]'s effect to impede phosphoinositide
synthesis since it also was reversed by guanosine or adenosine.
Received 14 March 1997; accepted in final form 7 July 1997.
APS Manuscript Number E116-7.
Article publication pending Am. J. Physiol. (Endocrinol. Metab.).
ISSN 1080-4757 Copyright 1997 The American Physiological Society.
Published in APStracts on 24 July 1997