Cyclic-AMP modulates downstream events in CD40-mediated signal transduction, but inhibition of protein kinase A has no direct effect on CD40 signaling

The role of cAMP/protein kinase A (PKA) in CD40 signal transduction is controversial, with evidence both for and against its importance. In this study we have used a tetracycline-repressible expression system to reversibly express a dominant-negative form of the PKA regulatory subunit type I (PKA-R(G324D)) in a B lymphoma line, M12. Expression of PKA-R(G324D) in M12 lymphomas inhibits both cAMP-mediated growth inhibition and cAMP-mediated induction of B7-2. This inhibition is reversed by tetracycline treatment of the cells to turn off inhibitor expression. In contrast, the expression of the PKA-R(G324D) subunit has no effect on CD40-mediated growth inhibition in M12 cells, nor on CD40-mediated induction of B7-1, CD23, Fas, ICAM-1, or LFA-1. Thus, our data do not support a direct role for cAMP/PKA in CD40-mediated signal transduction. However, we do observe that cAMP can regulate CD40 signaling both positively and negatively. Cyclic-AMP synergizes with CD40-mediated B7-1 induction in M12 lymphomas, while inhibiting CD40-mediated CD23, Fas, and ICAM-1 induction.