Involvement of exchange protein directly activated by cAMP and tumor progression locus 2 in IL-1β production in microglial cells following activation of β-adrenergic receptors

Endogenous noradrenaline (NA) has multiple bioactive functions and, in the central nervous system (CNS), has been implicated in modulating neuroinflammation via beta-adrenergic receptors (beta-ARs). Microglia, resident macrophages in the CNS, have a central role in the brain immune system and have been reported to be activated by NA. However, intracellular signaling mechanisms of the AR-mediated proinflammatory responses of microglia are not fully understood. Using a rapid and stable in vitro reporter assay system to evaluate IL-1beta production in microglial BV2 cells, we found that NA and the beta-AR agonist isoproterenol upregulated the IL-1beta reporter activity. This effect was suppressed by beta-AR antagonists. We further examined the involvement of EPAC (exchange protein directly activated by cAMP) and TPL2 (tumor progression locus 2, MAP3K8) and found that inhibitors for EPAC and TPL2 reduced AR agonist-induced IL-1beta reporter activity. These inhibitors also suppressed NA-induced endogenous Il1b mRNA expression and IL-1beta protein production. Our results suggest that EPAC and TPL2 are involved in beta-AR-mediated IL-1beta production in microglial cells, and extend our understanding of its intracellular signaling mechanism.