TY - JOUR
T1 - Stimulation of interleukin-12 production in mouse macrophages via activation of p38 mitogen-activated protein kinase by α2-adrenoceptor agonists
AU - Kang, Bok Yun
AU - Lee, Seung Won
AU - Kim, Tae Sung
N1 - Funding Information:
The authors thank Drs. S. Wolf, Y.K. Choe, and J. Cheong for their generous gift of valuable reagents, and Drs. E.P. Cohen, J.W. Lee, and Y.C. Lee for helpful discussions and critical reading. This work was supported by a grant from the Korea Health 21 R&D Project, Ministry of Health and Welfare, Republic of Korea (01-PJ1-PG3-21200-0021).
PY - 2003/4/25
Y1 - 2003/4/25
N2 - 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.
AB - 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.
KW - Interleukin-12
KW - Macrophage
KW - P38 Mitogen-activated protein kinase
KW - α-Adrenoceptor agonist
UR - http://www.scopus.com/inward/record.url?scp=0037466475&partnerID=8YFLogxK
U2 - 10.1016/S0014-2999(03)01628-5
DO - 10.1016/S0014-2999(03)01628-5
M3 - Article
C2 - 12706479
AN - SCOPUS:0037466475
VL - 467
SP - 223
EP - 231
JO - European Journal of Pharmacology
JF - European Journal of Pharmacology
SN - 0014-2999
IS - 1-3
ER -