SUPPRESSION OF TNF-ALPHA EXPRESSION, INHIBITION OF TH1 ACTIVITY, AND AMELIORATION OF COLLAGEN-INDUCED ARTHRITIS BY ROLIPRAM

Rolipram is a type IV phosphodiesterase inhibitor that suppresses infl ammation and TNF-alpha production. As anti-TNF-alpha therapy is effect ive in rheumatoid arthritis, we investigated the effect of rolipram on collagen-induced arthritis (CIA), a murine model of rheumatoid arthri tis. Rolipram was administered after the onset of clinical arthritis a t doses of 0.5, 3, 5, or 10 mg/kg twice daily, with a dose-dependent t herapeutic effect on clinical severity and joint erosion. Immunohistoc hemical analysis of joints of rolipram-treated mice revealed 67% reduc tion in TNF-alpha-expressing cells compared with control arthritic mic e. In vitro studies using bone marrow-derived macrophages confirmed th at rolipram directly suppressed TNF-alpha and IL-12 production followi ng stimulation with IFN-gamma and LPS. The effect of rolipram on T cel l activity was studied by measuring Th1/Th2 cytokine production by col lagen-stimulated draining lymph node cells from arthritic mice treated in vivo with rolipram. Rolipram reduced IFN-gamma production and incr eased IL-10, indicating that rolipram down-regulated the ongoing Th1 r esponse to type II collagen. Finally, the effect on CIA of combination therapy was studied using rolipram plus either anti-TNF-alpha or anti -CD4 mAbs. Rolipram plus anti-TNF-alpha was not therapeutically additi ve, whereas rolipram plus anti-CD4 mAb was clearly additive. This resu lt indicates that the therapeutic effects of rolipram overlap with TNF -alpha blockade, but are complementary to anti-CD4 treatment. It is th erefore proposed that a major mechanism of action of rolipram in CIA i s suppression of TNF-alpha activity. These findings suggest that type IV phosphodiesterase inhibitors may be effective in pathologic conditi ons, such as RA, with overexpression of TNF-alpha.