Antidiabetogenic effect of pentoxifylline is associated with systemic and target tissue modulation of cytokines and nitric oxide production

We have shown recently that xanthine derivative pentoxifylline (PTX) downre gulates an inflammatory autoimmune process triggered in genetically suscept ible Dark Agouti rats by multiple low doses of streptozotocin (MLD-SZ, 20 m g/kg/day ip for 5 days). We studied the cellular and molecular consequences of PTX treatment during MLD-SZ-induced diabetes with special emphasis on l ocal vs. systemic production of inflammatory mediators. Administration of P TX (200 mg/kg/day for 10 days) during induction of the disease reduced clin ical signs of diabetes and protected rats from development of destructive i ntrainsulitis. Pentoxifylline did not affect diabetogenic effect of single high dose of SZ (100 mg/kg SZ). Ex vivo analysis of the islets of Langerhan s performed in early disease development revealed that PTX downregulates pr oduction of proinflammatory cytokines IFN-gamma and TNF, as well as inducib le nitric oxide synthase (iNOS) expression and NO production. In addition, PTX treatment suppressed splenocyte autoreactivity, as well as the frequenc y of cells expressing IL-2R and MHC class II antigens. There was no evidenc e of any changes in proportion of ICAM-1 and LFA-1 expressing splenocytes i n comparison to control MLD-SZ-treated animals. In contrast to suppressed i ntraislet production, high peripheral expression of both iNOS mRNA and NO w as found in MLD-SZ rats treated with PTX. Taken together, the data indicate that the effect on both systemic and intra-islet production of NO, suppres sion of autoreactive cell activation and of local type 1 cytokine release m ay contribute to the therapeutic benefit achieved by PTX in the rat. (C) 20 01 Academic Press.