Natural mediators that elevate the cAMP pathway and lead to PKA activation include PGE2 (mainly via the G protein-coupled receptors E2 and E4 on T cells) and adenosine (mainly via the A 2A receptor on T cells). Both mediators are produced at sites of immune inflammation, adenosine by degradation of ATP from dying cells, and PGE2 by activated macrophages. PKA activation signals also synergized with TCR signals to induce HB-EGF mRNA and protein expression in human CD4 T cells (data not shown). Thus during the progression of an inflammatory response, there may be a switch from pro-inflammatory cytokine production to AR (and HB-EGF) production.