AJP - Cell Physiology, Vol 263, Issue 1 C114-C120, Copyright © 1992 by American Physiological Society
Differential effects of cytokines on long-term mitogenic and secretory responses of fetal rat pancreatic beta-cells
A. Sjoholm
Department of Medical Cell Biology, Uppsala University, Sweden.
It has been proposed that certain cytokines secreted by islet-infiltrating
leukocytes may be involved in the pathogenesis of insulin-dependent
diabetes mellitus by participation in beta-cell destruction. In the present
study, the impact of various cytokines on replication and long-term insulin
secretion by pancreatic beta-cells was investigated. To this end, fetal rat
pancreatic islets containing a high fraction of beta-cells were exposed in
culture for 1-3 days to interleukin-1 beta (IL-1 beta), tumor necrosis
factor-alpha (TNF-alpha), interferon-gamma (IFN-gamma), interferon-alpha
(IFN-alpha), and interleukin-6 (IL-6) at different concentrations. It was
found that IL-1 beta markedly decreased beta-cell DNA synthesis during the
first day of exposure, an effect that vanished after 2 days and was turned
into a potent and dose-dependent stimulation by 3 days of exposure. At this
latter time point, IL-1 beta also amplified the mitogenicity of growth
hormone (GH) and 16.7 mM glucose. In contrast, basal as well as glucose-
and GH-stimulated insulin secretion was consistently suppressed by IL-1
beta from days 1-3. IL-1 beta also lowered the islet adenosine 3',5'-cyclic
monophosphate (cAMP) content at all time points studied. However, addition
of the stimulatory cAMP analogue Sp-diastereomer of adenosine 3',5'-cyclic
monophosphothioate or pertussis toxin, which themselves enhanced DNA
synthesis and insulin secretion, failed to prevent the inhibitory actions
of IL-1 beta on these parameters, making it unlikely that a decrease in
cAMP is an important event in transduction of the inhibitory effects of the
cytokine.(ABSTRACT TRUNCATED AT 250 WORDS)
