Stimulation of Unprimed Macrophages with Immune Complexes Triggers a Low Output of Nitric Oxide by Calcium-dependent Neuronal Nitric-oxide Synthase

被引:48
作者
Huang, Zhi [1 ,3 ]
Hoffmann, FuKun W. [1 ]
Fay, Jeffrey D. [1 ]
Hashimoto, Ann C. [1 ]
Chapagain, Moti L. [2 ]
Kaufusi, Pakieli H. [2 ]
Hoffmann, Peter R. [1 ]
机构
[1] Univ Hawaii, John A Burns Sch Med, Dept Cell & Mol Biol, Honolulu, HI 96813 USA
[2] Univ Hawaii, John A Burns Sch Med, Dept Trop Med Med Microbiol & Pharmacol, Honolulu, HI 96813 USA
[3] Jinan Univ, Coll Life Sci & Technol, Dept Biotechnol, Guangzhou 510632, Guangdong, Peoples R China
基金
中国国家自然科学基金; 美国国家卫生研究院;
关键词
MURINE MACROPHAGES; MAMMALIAN-CELLS; L-ARGININE; GAMMA; PHAGOCYTOSIS; EXPRESSION; LOCATION; DYSFUNCTION; ACTIVATION; INHIBITION;
D O I
10.1074/jbc.M111.315598
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Immune complexes composed of IgG-opsonized pathogens, particles, or proteins are phagocytosed by macrophages through Fc gamma receptors (Fc gamma Rs). Macrophages primed with IFN gamma or other pro-inflammatory mediators respond to Fc gamma R engagement by secreting high levels of cytokines and nitric oxide (NO). We found that unprimed macrophages produced lower levels of NO, which required efficient calcium (Ca2+) flux as demonstrated by using macrophages lacking selenoprotein K, which is required for Fc gamma R-induced Ca2+ flux. Thus, we further investigated the signaling pathways involved in low output NO and its functional significance. Evaluation of inducible, endothelial, and neuronal nitric-oxide synthases (iNOS, eNOS, and nNOS) revealed that Fc gamma R stimulation in unprimed macrophages caused a marked Ca2+-dependent increase in both total and phosphorylated nNOS and slightly elevated levels of phosphorylated eNOS. Also activated were three MAP kinases, ERK, JNK, and p38, of which ERK activation was highly dependent on Ca2+ flux. Inhibition of ERK reduced both nNOS activation and NO secretion. Finally, Transwell experiments showed that Fc gamma R-induced NO functioned to increase the phagocytic capacity of other macrophages and required both NOS and ERK activity. The production of NO by macrophages is conventionally attributed to iNOS, but we have revealed an iNOS-independent receptor/enzyme system in unprimed macrophages that produces low output NO. Under these conditions, Fc gamma R engagement relies on Ca2+-dependent ERK phosphorylation, which in turn increases nNOS and, to a lesser extent, eNOS, both of which produce low levels of NO that function to promote phagocytosis.
引用
收藏
页码:4492 / 4502
页数:11
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