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 t o reversibly express a dominant-negative form of the PKA regulatory su bunit type I (pKA-R-G324D) in a B lymphoma line, M12. Expression of pK A-R-G324D in M12 lymphomas inhibits both cAMP-mediated growth inhibiti on 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 transductio n. However, we do observe that cAMP can regulate CD40 signaling both p ositively and negatively. Cyclic-AMP synergizes with CD40-mediated B7- 1 induction in M12 lymphomas, while inhibiting CD40-mediated CD23, Fas , and ICAM-1 induction.