A forskolin-mediated increase in cAMP promotes T helper cell differentiation into the Th1 and Th2 subsets rather than into the Th17 subset

The cyclic adenosine monophosphate (cAMP) signaling pathway is involved in various physiological and pathophysiological processes. Forskolin (FSK), a labdane diterpene well known as an activator of cAMP production, is suggested to possess significant immunomodulatory potential. However, the specific effects of elevated cAMP levels caused by the FSK-mediated activation of adenylate cyclase (AC) on T helper (Th) cell differentiation and functions are still unclear. We speculated that the increased levels of cAMP in Th cells affect the differentiation program of distinct Th populations differently, in particular the development of Th1, Th2, and Th17 subsets. Only minor changes in the expressions of isoforms of ACs and phosphodiesterases (PDE), enzymes responsible for the degradation of cAMP, were observed in differentiating human Th cells with prevailing ADCY1, ADCY3, ADCY7 , and ADCY9 and PDE3B , PDE4A/B/D , PDE7A/B , and PDE8A isoforms. FSK mediated elevation in Th1-specific markers reinforcing the Th1 cell phenotype. The differentiation of Th2 was not altered by FSK, though cell metabolism was affected. In contrast, the Th17 immunophenotype was severely suppressed leading to the highly specific upregulation of the level of CXCL13. The causality between FSK-elicited cAMP production and the observed modulation of Th2 differentiation was proven by using cAMP inhibitor 2’,5’-dideoxyadenosine that reverted the FSK effects. Overall, an FSK-mediated cAMP increase has an effect on Th1, Th2 and Th17 differentiation and can contribute to the identification of novel therapeutic targets for the treatment of Th cell-related pathological processes.