Stimulation of interleukin-12 production in mouse macrophages via activation of p38 mitogen-activated protein kinase by α2-adrenoceptor agonists

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 alpha(2)-adrenoceptor agonists are involved in the induction of interleukin-12 production by macrophages. alpha(2)-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 alpha(2)-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 alpha(2)-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), alpha(2)-adrenoceptor antagonists, significantly blocked agonist-induced interleukin-12 production and p38 MAPK activation, indicating that the effects of the agonists were mediated through alpha2-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 alpha(2)-adrenoceptor agonists induce interleukin-12 production in mouse macrophages via a PKC/p38 MAPK signaling pathway and suggest that the effect of alpha(2)-adrenoceptor agonists on interleukin-12 secretion may be a new and novel means of augmenting cell-mediated immune responses. (C) 2003 Elsevier Science B.V. All rights reserved.