Figure 11: Regulatory role of cAMP in TGF-β induced expression of FoxP3 and differentiation of adaptive Tregs. Cyclic AMP suppresses TGF-β-induced expression of Foxp3 by at least two mechanisms. TGF-β activates ERK and JNK, but not p38 signaling pathways. ERK and JNK induce transcription factors that induce transcription of Foxp3 genes to induce expression of FoxP3. Cyclic AMP blocks TGF-β-induced activation of ERK in a PKA-dependent and CREB independent manner. In contrast, cAMP inhibits JNK induced FoxP3 expression through a transcription-dependent manner. Thus, by these two mechanisms cAMP suppresses TGF-β-mediated differentiation of adaptive Treg cells. (Green arrows, excitatory; red arrows, inhibitory).