CYCLIC-AMP IS AN ESSENTIAL FACTOR IN IMMUNE-RESPONSES

In the present studies, cAMP, a secondary messenger historically viewe d as a negative mediator of immune responses, was demonstrated to poss ess immunoenhancing activity at low concentrations. In parallel experi ments the adenylate cyclase inhibitor, 2',3'-dideoxyadenosine, produce d a marked inhibition of humoral and proliferative immune responses su ggesting that cAMP at physiologically relavent concentrations acts as a critical second messenger in immune responses. Direct addition of di butyryl cAMP (10 - 100 mu M), a membrane permeable cAMP analog, to mou se spleen cell cultures produced a marked and dose-related increase (2 5-100%) in humoral immune responses as measured by the primary IgM ant ibody forming cell response to the antigen, sheep erythrocytes. Over a similar concentration range, dibutyryl cAMP (5 - 50 mu M) also dose-d ependently enhanced (25-50%) phorbol 12-myristate 13-acetate/ionomycin -stimulated lymphoproliferation. Incubation of spleen cells with 2',3' -dideoxyadenosine (40 - 80 mu M), an adenylate cyclase inhibitor, for 30 min depressed significantly the basal level of intracellular cAMP. 2',3'-dideoxyadenosine treatment also significantly decreased both the antibody forming cell response and the proliferative response in a do se-dependent manner. Interestingly, the antibody forming cell response exhibited significantly greater sensitivity to inhibition by 2',3'-di deoxyadenosine than the lymphoproliferative responses. The critical ro le for cAMP as a positive immunoregulatory signal is further supported by the fact that the immunosuppression by 2',3'-dideoxyadenosine coul d be reversed completely in the antibody forming cell response to shee p erythrocytes through the addition of dibutyryl cAMP into the culture medium. Partial but not complete reversal of the inhibitory effects o f 2',3'-dideoxyadenosine on lymphoproliferation was also demonstrated by dibutyryl cAMP. Taken together, these results suggest that cAMP act s as a positive regulatory signal for immune responses as indicated by the fact that depletion of intracellular cAMP induces a marked inhibi tion of humoral and proliferative responses. (C) 1995 Academic Press, Inc.