A naturally occurring 6-9-kilodalton interleukin-1 (IL-1) inhibitor prevents IL-1-mediated islet cytotoxicity but not IL-1-mediated suppression of insulin secretion.
Earlier studies have shown direct effects of interleukin-1 (IL-1) on isolated pancreatic islets. Coculture of isolated rat pancreatic islets with human rIL-1 beta for 6 days resulted in dose-dependent cytotoxicity (up to 100%) and suppression of insulin secretion (up to 88.5%). The cytotoxic effects of rIL-1 beta beta were blocked by the simultaneous presence of a naturally occurring 6-9-kilodalton (kDa) inhibitor of IL-1-induced T-cell proliferation. However, the ability of rIL-1 beta to suppress insulin secretion was not blocked by the 6-9-kDa inhibitor of IL-1 activity. This IL-1 inhibitor is produced by mononuclear cells and is resistant to pH 2, sensitive to heating at 56 degrees C for 30 min, has a pI of 4.5-5.6, and appears to be different from other recognized IL-1 inhibitors in both composition and mechanism of action. Unlike this IL-1 inhibitor, a monoclonal antibody specific for rIL-1 beta was able to neutralize both the islet cytotoxic and insulin modulatory effects of rIL-1 beta. These results demonstrate the use of an IL-1 inhibitor to prevent at least one mechanism of islet destruction, and suggest separate pathways for IL-1 mediated islet cytotoxicity and suppression of insulin secretion.
Kawahara
D J
DJ
Diabetes Research Laboratory, Children's Hospital of Orange County, CA 92668.
Everts
M
M
Buckingham
B
B
Sandborg
C
C
Berman
M
M
D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology; D000918:Antibody Specificity / Q000276:immunology; D000937:Antigen-Antibody Reactions / Q000276:immunology; D066298:In Vitro Techniques; D007328:Insulin / Q000276:immunology / Q000378:metabolism*; D000078790:Insulin Secretion; D007375:Interleukin-1 / Q000037:antagonists & inhibitors*; D007515:Islets of Langerhans / Q000187:drug effects* / Q000378:metabolism; D008970:Molecular Weight; D051381:Rats; D011919:Rats, Inbred Strains; D011994:Recombinant Proteins / Q000037:antagonists & inhibitors
D000911:Antibodies, Monoclonal; D007328:Insulin; D007375:Interleukin-1; D011994:Recombinant Proteins