Cyclic AMP suppresses TGF-β-mediated adaptive Tregs differentiation through inhibiting the activation of ERK and JNK

• We examined the role of cAMP in TGF-β-induced Foxp3 expression in murine T cells.
• cAMP suppresses TGF-β-induced expression of Foxp3.
• Site-selective PKA activator 6-MB-cAMP mimics cAMP’s effect on Foxp3 expression.
• cAMP and 6-MB-cAMP block TGF-β-induced activation of ERK and JNK.
• Direct inhibition of ERK or JNK activity dampens TGF-β-induced expression of Foxp3.

The second messenger cAMP is involved in the regulation of many cellular activities partially through modulating the MAPK pathways. The role of cAMP in TGF-β-mediated adaptive Tregs differentiation remains elusive. In this work, we show that cAMP inhibits antigen-nonspecific proliferation of murine CD4+ T cells without significant promotion of apoptosis. Moreover, cAMP suppresses TGF-β-induced expression of forkhead transcription factor Foxp3. 6-MB-cAMP, a site-selective activator of PKA, mimics the role of cAMP in TGF-β-induced Foxp3 expression. Further exploration reveals that TGF-β activates ERK and JNK, but not p38. cAMP and 6-MB-cAMP block TGF-β-induced activation of ERK and JNK through transcription-independent manner and transcription-dependent manner, respectively. Since direct inhibition of ERK or JNK activity mimics the effects of cAMP during this process, our work suggests that cAMP suppresses TGF-β-mediated adaptive Tregs differentiation through, at least partially, inhibiting the activation of ERK and JNK.