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

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.