The effect of cytokines on expression of glutamic acid decarboxylase-65 in cultured islets.
Insulin dependent diabetes mellitus (IDDM) is an autoimmune disease characterized by lymphocytic infiltration of the pancreatic islets (insulitis). Cytokines released as part of the insulitis process have been suggested to play an important role in the beta cell lesion of IDDM. A possible diabetogenic effect of cytokines may be mediated by their inducing abnormal expression of islet cell autoantigens. Since glutamic acid decarboxylase-65 (GAD-65) is a target autoantigen in IDDM, we investigated whether the cytokines IL-1 beta, TNF alpha IFN gamma altered islet cell expression of GAD-65 and whether the effect of cytokines on GAD-65 expression was similar to their effect on insulin secretion. We found that: 1) IL-1 beta at low dose (1 U/ml) which stimulated insulin secretion, had no effect on GAD-65 expression, whereas higher doses of IL-1 beta (10, 100, 1000 U/ml) which inhibited insulin secretion, decreased GAD-65 expression. 2) TNF alpha at doses of 10, 100, 1000 U/ml which stimulated insulin secretion had no effect on GAD-65 expression. 3) IFN gamma at doses of 10, 100, 1000 U/ml had no effect on insulin secretion or on GAD-65 expression. 4) In combination, IL-1 beta plus TNF alpha and IFN gamma showed a similar inhibitory effect on GAD-65 expression as IL-1 beta alone. In summary: 1) IL-1 beta dramatically inhibits GAD-65 expression. 2) TNF alpha and IFN gamma have no effect on GAD-65 expression. Of these three cytokines, IL-1 beta is the primary cytokine affecting GAD-65 expression.
Hao
W
W
Veterans Affairs Medical Centre, Seattle, WA 98108, USA.
Palmer
J P
JP
D000818:Animals; D016207:Cytokines / Q000494:pharmacology*; D005968:Glutamate Decarboxylase / Q000819:agonists / Q000096:biosynthesis* / Q000187:drug effects; D018840:HSP70 Heat-Shock Proteins / Q000032:analysis; D015151:Immunoblotting; D007371:Interferon-gamma / Q000494:pharmacology; D007375:Interleukin-1 / Q000494:pharmacology; D007515:Islets of Langerhans / Q000187:drug effects* / Q000378:metabolism*; D008297:Male; D009924:Organ Culture Techniques; D051381:Rats; D017207:Rats, Sprague-Dawley; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
D016207:Cytokines; D018840:HSP70 Heat-Shock Proteins; D007375:Interleukin-1; D014409:Tumor Necrosis Factor-alpha; D007371:Interferon-gamma; D005968:Glutamate Decarboxylase