Polarized Th1 and Th2 cells are less responsive to negative feedback by receptors coupled to the AC/cAMP system compared to freshly isolated T cells

The adenylyl cyclase (AC)/cyclic adenosine monophosphate (cAMP) system is known to negatively regulate transcriptional activity of T cells, thereby possibly modulating T‐cell‐mediated responses at the sites of inflammation. Effects of cAMP have been widely studied in freshly isolated T cells and T‐cell clones; yet, effects in differentiated Th1 and Th2 cells are largely unknown. To obtain differentiated T helper cells, we activated naive T cells for 1 week in the presence of IL‐12 plus α‐IL‐4 to generate Th1‐type cells and in the presence of IL‐4 plus α‐IL‐12 to generate Th2‐type cells. We demonstrate that, in contrast to freshly isolated T cells, the production of Th1 (IFN‐γ) and Th2 (IL‐4, IL‐5) cytokines in polarized T helper cells is not strictly controlled by the activation of AC/cAMP‐linked β2‐adrenergic and prostaglandin (PG)E2 receptors. In Th2 cells, PGE2 could still activate the Gs protein‐coupled AC/cAMP system and subsequently induce CREB phosphorylation, whereas PGE2 was unable to activate the cAMP‐dependent pathway in Th1 cells. In both Th1 and Th2 cells, the induction of CREB phosphorylation by β2‐agonist fenoterol was impaired. The loss of control over cytokine production by cAMP elevating agents in differentiated Th1 and Th2 subsets may have important implications for the regulation of Th1‐ and Th2‐mediated diseases, in particular those associated with the ongoing immune responses. British Journal of Pharmacology (2003) 138, 1441–1450. doi:10.1038/sj.bjp.0705193