A carbocyclic nucleoside analogue is a TNF-α inhibitor with immunosuppressive action:: Role of prostaglandin E2 and protein kinase C and comparison with pentoxifylline

Tumor necrosis factor-alpha (TNF-alpha) is associated with several acute and chronic inflammatory conditions. New therapies directed at inhibiting TNF-alpha will be important in treating pathological processes mediated by TNF-alpha. In this study, we studied and compared the effect of the carbocyclic nucleoside analogue (9-[(1R,3R)-trans-cyclopentan-3-ol] adenine) with pentoxifylline on modulating TNF-alpha production. The carbocyclic nucleoside analogue inhibited TNF-alpha production in a dose-dependent manner (1 mu M-1 mM) by stimulated peripheral blood mononuclear cells and cell lines of both monocyte (THP-1) and T-lymphocyte phenotypes (CEM x 174). The drug potently inhibited TNF production in cells stimulated by endotoxin, the superantigen (staphylococci enterotoxin A), the mitogen (phytohemagglutinin), and the protein kinase C activator (phorbol myristate acetate) with ED50 ranging from 5 to 30 mu M. At moderate concentrations, the carbocyclic nucleoside analogue inhibited superantigen (ED50 300 mu M) and alloantigen (mixed lymphocyte reaction) T cell proliferative responses (ED50 = 150 mu M). The involvement of protein kinase C and prostaglandin E-2 (PGE(2)), mediators that regulate TNF-alpha production, was also investigated. Unlike PTX, the nucleoside analogue did not upregulate PGE(2) production, The inhibition of TNF-alpha production appeared to be mediated at least partly by PBC, since the nucleoside analogue caused suppression of PKC activity in stimulated cells. The results show that the carbocyclic nucleoside analogue is a TNF-alpha inhibitor that may be appropriate in the therapy of TNF-alpha-associated complications. The suppressive properties of the carbocyclic nucleoside analogue on antigen and alloantigen (mixed lymphocyte reaction) responses may be appropriate in disease conditions in which inhibiting both TNF-alpha and T-cell reactivity is desirable, (C) 1998 Academic Press.