THE PHOSPHODIESTERASE INHIBITORS PENTOXIFYLLINE AND ROLIPRAM PREVENT DIABETES IN NOD MICE

Interleukin (IL)-12, interferon (IFN)-gamma, and other inflammatory cy tokines play an important role in the pathogenesis of autoimmune insul itis and diabetes in NOD mice, and inhibition of these cytokines is li kely to be beneficial. In this study, we found that Pentoxifylline (PT X) and Rolipram (phosphodiesterase [PDE] inhibitors that induce increa sed intracellular cAMP) can block inflammatory cytokine production. In hibition of IL-12 and IFN-gamma secretion was demonstrated in macropha ges activated with lipopolysaccharide or T-cells stimulated through th e CD3/T-cell receptor complex, respectively. Moreover, strong inhibiti on of IL-12 was demonstrated in vivo in superantigen-immunized mice. R olipram was inhibitory at concentrations as low as 10(-8) to 10(-7) mo l/l, and on a molar basis, it was 100-fold more effective than PTX. Tu mor necrosis factor-alpha was also inhibited, but IL-4 was less sensit ive to suppression. In NOD mice, both PTX and Rolipram reduced the sev erity of insulitis and prevented diabetes, with or without cyclophosph amide administration (which precipitates onset of disease). This prote ction of NOD mice was still apparent over 10 weeks after withdrawal of the drug treatment. It appears that blocking the activity of type IV PDE is sufficient to mediate the effects reported in this study, since Rolipram inhibits only this isoform, unlike PTX (a general inhibitor) . PTX and Rolipram may be effective in the treatment of autoimmune dia betes or other conditions characterized by excessive production of inf lammatory cytokines.