A Carbocyclic Nucleoside Analogue Is a TNF-α Inhibitor with Immunosuppressive Action: Role of Prostaglandin E2and Protein Kinase C and Comparison with Pentoxifylline

Abstract

Tumor necrosis factor-α (TNF-α) is associated with several acute and chronic inflammatory conditions. New therapies directed at inhibiting TNF-α will be important in treating pathological processes mediated by TNF-α. 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-α production. The carbocyclic nucleoside analogue inhibited TNF-α production in a dose-dependent manner (1 μM–1 mM) by stimulated peripheral blood mononuclear cells and cell lines of both monocyte (THP-1) and T-lymphocyte phenotypes (CEM × 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 ED50ranging from 5 to 30 μM. At moderate concentrations, the carbocyclic nucleoside analogue inhibited superantigen (ED50= 300 μM) and alloantigen (mixed lymphocyte reaction) T cell proliferative responses (ED50= 150 μM). The involvement of protein kinase C and prostaglandin E2(PGE2), mediators that regulate TNF-α production, was also investigated. Unlike PTX, the nucleoside analogue did not upregulate PGE2production. The inhibition of TNF-α production appeared to be mediated at least partly by PKC, since the nucleoside analogue caused suppression of PKC activity in stimulated cells. The results show that the carbocyclic nucleoside analogue is a TNF-α inhibitor that may be appropriate in the therapy of TNF-α-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-α and T-cell reactivity is desirable.