Stimulation of interleukin-12 production in mouse macrophages via activation of p38 mitogen-activated protein kinase by alpha2-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 alpha(2)-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.
Kang
Bok Yun
BY
Immunology Laboratory, College of Pharmacy and Research Institute of Drug Development, Chonnam National University, Kwangju 500-757, Republic of Korea.
Lee
Seung Won
SW
Kim
Tae Sung
TS
D000262:Adenylyl Cyclases / Q000502:physiology; D058647:Adrenergic alpha-2 Receptor Agonists; D000818:Animals; D003000:Clonidine / Q000494:pharmacology; D004789:Enzyme Activation; D005260:Female; D016316:Guanfacine / Q000494:pharmacology; D066298:In Vitro Techniques; D018664:Interleukin-12 / Q000096:biosynthesis*; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism*; D051379:Mice; D008811:Mice, Inbred DBA; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism* / Q000502:physiology; D010109:Oxymetazoline / Q000494:pharmacology; D011493:Protein Kinase C / Q000502:physiology; D012333:RNA, Messenger / Q000096:biosynthesis; D018341:Receptors, Adrenergic, alpha-2 / Q000502:physiology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013154:Spleen / Q000166:cytology; D048051:p38 Mitogen-Activated Protein Kinases
D058647:Adrenergic alpha-2 Receptor Agonists; D012333:RNA, Messenger; D018341:Receptors, Adrenergic, alpha-2; D018664:Interleukin-12; D016316:Guanfacine; D010109:Oxymetazoline; D011493:Protein Kinase C; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D000262:Adenylyl Cyclases; D003000:Clonidine