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Th2 Cytokines Have a Partial, Direct Protective Effect on the Function and Survival of Isolated Human Islets Exposed to Combined Proinflammatory and Th1 Cytokines

Dipartimento di Endocrinologia e Metabolismo, Sezione Metabolismo, Università di Pisa (L.M., M.M., R.L., S.D.G., R.N., P.M.), 56100 Pisa; Dipartimento di Scienze Cliniche, Università La Sapienza, Roma (F.D., C.S., M.R.), Roma; Cattedra di Endocrinologia e Patologia Costituzionale, Università di Catania (S.P., F.P.), Catania; and Dipartimento di Oncologia, Università di Pisa (F.M., U.B.), Pisa, Italy

Address all correspondence and requests for reprints to: Piero Marchetti, M.D., Dipartimento di Endocrinologia e Metabolismo, Ortopedia e Traumatologia, Medicina del Lavoro (Sezione Metabolismo), via Paradisa 2, Ospedale Cisanello, 56100 Pisa, Italy. E-mail: marchant{at}immr.med.unipi.it

Abstract

Studies in rodents have suggested that Th2 and Th3 cytokines can be effective in reducing proinflammatory and Th1 cytokine-induced islet damage. Whether this is the case with human islets and might be due to a direct action of Th2 and Th3 cytokines is not known. In the present study, we evaluated whether Th2 (500 U/ml IL-4 plus 100 U/ml IL-10) or Th3 (5 ng/ml TGF-1ß) cytokines may prevent the derangements induced on isolated human islets by prolonged (12 or 72 h) exposure to combined proinflammatory (50 U/ml IL-1ß, 1000 U/ml TNF ) and Th1 (1000 U/ml interferon ) cytokines. Compared with control islets, cells preincubated for 12 or 72 h with proinflammatory and Th1 cytokines showed a significant decrease of glucose-stimulated insulin secretion and a significant increase of nitrites production. The addition of IL-4 plus IL-10 or TGF-1ß in the medium prevented these cytostatic effects in the 12-h incubation experiments, but not after the 72-h exposure period. IL-1ß, interferon , and TNF caused no major change in either islet cell survival or Bcl-2 and Bax mRNA expression after a 12-h incubation; however, a marked increase in the amount of dead cells, with a major decrease of Bcl-2 mRNA expression, was observed after 72 h. The presence of Th2, but not of Th3, cytokines significantly reduced ß-cell death, without any major effect on Bcl-2 and Bax mRNA expression. These results suggest that Th2 and (at lower extent) Th3 cytokines may have a partial, direct protective effect on isolated human islets exposed to the cytostatic and cytotoxic action of proinflammatory and Th1 cytokines.

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