Differential expression of inducible nitric oxide synthase and IL-12 between peritoneal and splenic macrophages stimulated with LPS plus IFN-gamma is associated with the activation of extracellular signal-related kinase.
Resident peritoneal macrophages (pMphi) are found deficient in T cell-stimulating capacity compared with the competent splenic macrophages (sMphi). Macrophages (Mphi)-derived nitric oxide (NO) and IL-12 have been shown to play crucial roles in the interaction between Mphi and T cells. To further understand differential functions between pMphi and sMphi, we focused on the production of NO and IL-12 from LPS plus IFN-gamma-activated Mphi. We demonstrated the differential expression of inducible nitric oxide synthase (iNOS) and IL-12 in pMphi and sMphi with LPS plus IFN-gamma stimulation. pMphi produced high level of NO but low level of IL-12, whereas sMphi produced high level of IL-12 but no NO. Furthermore, we demonstrated that there were no differences in IFN-gamma-induced signal transducer and activator of transcription-1 activation and consequent interferon regulatory factor-1 and interferon consensus sequence-binding protein up-regulation between pMphi and sMphi. Likewise, p38 mitogen-activated protein kinase was activated by LPS with identical kinetics in both pMphi and sMphi. However, LPS-induced extracellular signal-regulated kinase (ERK) activation was prolonged in pMphi comparing with sMphi. 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 pMphi. 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 pMphi possibly through suppressing ERK activation. Taken together, profound difference in ERK activation may account for differential LPS plus IFN-gamma responsiveness between pMphi and sMphi. High production of NO and low production of IL-12 by pMphi may contribute to its deficiency in T cell-stimulating capacity.
Zhu
Yi-Na
YN
Laboratory of Immunopharmacology, Graduate School of the Chinese Academy of Sciences, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Shanghai 201203, People's Republic of China.
Yang
Yi-Fu
YF
Ono
Shiro
S
Zhong
Xiang-Gen
XG
Feng
Yong-Hong
YH
Ren
Yong-Xin
YX
Ni
Jia
J
Fu
Yun-Feng
YF
Tang
Wei
W
Zuo
Jian-Ping
JP
D000818:Animals; D000970:Antineoplastic Agents / Q000276:immunology / Q000494:pharmacology*; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects* / Q000276:immunology; D007371:Interferon-gamma / Q000276:immunology / Q000494:pharmacology*; D018664:Interleukin-12 / Q000096:biosynthesis* / Q000276:immunology; D008070:Lipopolysaccharides / Q000276:immunology / Q000494:pharmacology*; D020935:MAP Kinase Signaling System / Q000187:drug effects* / Q000276:immunology; D017737:Macrophages, Peritoneal / Q000166:cytology / Q000276:immunology*; D051379:Mice; D008807:Mice, Inbred BALB C; D052247:Nitric Oxide Synthase Type II / Q000096:biosynthesis* / Q000276:immunology; D009928:Organ Specificity / Q000187:drug effects / Q000276:immunology; D013154:Spleen / Q000166:cytology / Q000276:immunology; D013601:T-Lymphocytes / Q000166:cytology / Q000276:immunology
D000970:Antineoplastic Agents; D008070:Lipopolysaccharides; D018664:Interleukin-12; D007371:Interferon-gamma; D052247:Nitric Oxide Synthase Type II