Interleukin-12 is a cytokine primarily produced by monocytes and macrophages. It plays an essential role in the development of cell-mediated immunity and stimulates T helper type 1 (Th1) immune responses. This study was designed to determine if α2-adrenoceptor agonists are involved in the induction of interleukin-12 production by macrophages. α2-adrenoceptor agonists such as clonidine, guanfacine, and oxymetazoline significantly induced interleukin-12 secretion and interleukin-12 mRNA expression by macrophages in a concentration-dependent manner. Moreover, stimulation of α2-adrenoceptor by their agonists triggered the activation of the p38 mitogen-activated protein kinase (MAPK) signaling pathway. Inhibitors of p38 MAPK prevented the stimulatory effects of α2-adrenoceptor agonists on IL-12 production. Yohimbine and 2-(2,3-dihydro-2-methoxy-1,4-benzodioxin-2-yl)4,5-dihydro-1H-imidazole (RX821002), α2-adrenoceptor antagonists, significantly blocked agonist-induced interleukin-12 production and p38 MAPK activation, indicating that the effects of the agonists were mediated through α2-adrenoceptor. In addition, protein kinase C (PKC) inhibitors, 1-(5-isoquinolinesulfonyl)-2-methylpiperazine dihydrochloride (H-7) and chelerythrine, significantly inhibited guanfacine-induced interleukin-12 production and p38 MAPK in a concentration-dependent manner. These findings show that α2-adrenoceptor agonists induce interleukin-12 production in mouse macrophages via a PKC/p38 MAPK signaling pathway and suggest that the effect of α2-adrenoceptor agonists on interleukin-12 secretion may be a new and novel means of augmenting cell-mediated immune responses.
- P38 Mitogen-activated protein kinase
- α-Adrenoceptor agonist
ASJC Scopus subject areas