International Immunology Advance Access originally published online on April 24, 2006
International Immunology 2006 18(6):981-990; doi:10.1093/intimm/dxl034
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Differential expression of inducible nitric oxide synthase and IL-12 between peritoneal and splenic macrophages stimulated with LPS plus IFN-
is associated with the activation of extracellular signal-related kinase
1 Laboratory of Immunopharmacology, Graduate School of the Chinese Academy of Sciences, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, 555 Zuchongzhi Road, Zhangjiang Hi-Tech Park, Shanghai 201203, People's Republic of China
2 Department of Oncology, Osaka University Graduate School of Medicine, 2-2, Yamada-oka, Suita, Osaka 565-0871, Japan
Correspondence to: J.-P. Zuo; E-mail: jpzuo{at}mail.shcnc.ac.cn
Resident peritoneal macrophages (pM
) are found deficient in T cell-stimulating capacity compared with the competent splenic macrophages (sM). Macrophages (M)-derived nitric oxide (NO) and IL-12 have been shown to play crucial roles in the interaction between M and T cells. To further understand differential functions between pM and sM, we focused on the production of NO and IL-12 from LPS plus IFN-
-activated M. We demonstrated the differential expression of inducible nitric oxide synthase (iNOS) and IL-12 in pM and sM with LPS plus IFN- stimulation. pM produced high level of NO but low level of IL-12, whereas sM produced high level of IL-12 but no NO. Furthermore, we demonstrated that there were no differences in IFN--induced signal transducer and activator of transcription-1 activation and consequent interferon regulatory factor-1 and interferon consensus sequence-binding protein up-regulation between pM and sM. Likewise, p38 mitogen-activated protein kinase was activated by LPS with identical kinetics in both pM and sM. However, LPS-induced extracellular signal-regulated kinase (ERK) activation was prolonged in pM comparing with sM. Moreover, we demonstrated, using inhibitor selective for ERK cascade (PD98059), that the prolonged ERK activation contributed a positive signal for iNOS expression and a negative signal for IL-12p40 expression in resident pM. In addition, anti-IL-10-neutralizing antibody plus indomethacin could abrogate the inhibitory effects of endogenous IL-10 and prostaglandin E2 on the production of IL-12 by resident pM possibly through suppressing ERK activation. Taken together, profound difference in ERK activation may account for differential LPS plus IFN- responsiveness between pM and sM. High production of NO and low production of IL-12 by pM may contribute to its deficiency in T cell-stimulating capacity.
Keywords: ERK, iNOS, IL-12, macrophage