Vk. Mehta et al., LOW-DOSE INTERLEUKIN-1 AND TUMOR-NECROSIS-FACTOR INDIVIDUALLY STIMULATE INSULIN RELEASE BUT IN COMBINATION CAUSE SUPPRESSION, European journal of endocrinology, 130(2), 1994, pp. 208-214
The macrophage-derived cytokines interleukin 1 (IL-1) and tumor necros
is factor (TNF) have direct effects on pancreatic beta cells and have
been hypothesized to play important roles in the autoimmune beta cell
lesion of type I diabetes because of two major effects on beta cells:
altered insulin secretion and beta cell cytotoxicity. High doses of IL
-1 are cytotoxic to beta cells and strongly inhibit insulin release; h
igh-dose IL-1 plus TNF acts synergistically to suppress further the in
sulin release. In contrast, we observed that the predominant effect of
low-dose IL-1 and TNF when administered separately was the stimulatio
n of insulin release. We therefore asked whether the combination of lo
w-dose IL-1 plus TNF would act synergistically to stimulate or suppres
s insulin release. Studies were performed on cultured rat islets and b
oth insulin release and cytotoxicity (Cr-51 release) were measured. Af
ter 2 days of culture, increasing doses of IL-1-25, 50, 75 and 100 ng/
l-caused progressively increased cytotoxicity and impaired insulin rel
ease. In contrast, the lowest dose of IL-1 tested, 10 ng/l, increased
insulin release but was still slightly cytotoxic. Tumor necrosis facto
r at doses of 10, 25, 62.5, 75 and 100 mu g/l also was slightly cytoto
xic but increased insulin release. The augmented insulin release decli
ned progressively with increasing TNF dose. However the combination of
insulin stimulatory doses of IL-1 (10 ng/l) and TNF (62.5 mu g/l) sup
pressed insulin release. The effects of these two cytokines on insulin
release demonstrated a similar pattern after 4 and 6 days of culture.
Although both IL-1 and TNF are cytotoxic to cultured islets cells, th
e effects of these two cytokines on insulin release are markedly diffe
rent; with IL-1 primarily suppressing and TNF increasing insulin relea
se. In combination, IL-1 and TNF always inhibits insulin release. The
lack of concordance between insulin release and cytotoxicity suggests
that these cytokines may alter insulin release by at least two mechani
sms, one dependent on and the other independent of cytotoxicity.