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The IFN-inducible GTPase LRG47 (Irgm1) negatively regulates TLR4-triggered proinflammatory cytokine production and prevents endotoxemia
被引:47
作者:
Bafica, Andre
Feng, Carl G.
Santiago, Helton C.
Aliberti, Julio
Cheever, Allen
Thomas, Karen E.
Taylor, Gregory A.
Vogel, Stefanie N.
Sher, Alan
机构:
[1] NIAID, Immunobiol Sect, Parasit Dis Lab, NIH, Bethesda, MD 20892 USA
[2] Univ Fed Santa Catarina, Dept Microbiol & Parasitol, Div Immunol, Florianopolis, SC, Brazil
[3] Univ Fed Minas Gerais, Belo Horizonte, MG, Brazil
[4] Childrens Hosp, Med Ctr, Div Mol Immunol, Cincinnati, OH 45229 USA
[5] Univ Maryland, Dept Microbiol & Immunol, Baltimore, MD 21201 USA
[6] Duke Univ, Ctr Geriatr Res Educ & Clin, VA Med Ctr, Durham, NC 27710 USA
[7] Duke Univ, Dept Med Immunol, Durham, NC 27710 USA
[8] Duke Univ, Dept Mol Genet & Microbiol, Durham, NC 27710 USA
[9] Duke Univ, Ctr Study Aging, Durham, NC 27710 USA
关键词:
D O I:
10.4049/jimmunol.179.8.5514
中图分类号:
R392 [医学免疫学];
Q939.91 [免疫学];
学科分类号:
100102 ;
摘要:
LRG47/Irgm1, a 47-kDa IFN-inducible GTPase, plays a major role in regulating host resistance as well as the hemopoietic response to intracellular pathogens. LRG47 expression in macrophages has been shown previously to be stimulated in vitro by bacterial LPS, a TLR4 ligand. In this study, we demonstrate that induction of LRG47 by LPS is not dependent on MyD88 signaling, but rather, requires STAT-1 and IFN-beta. In addition, LRG47-deficient mice are highly susceptible to LPS, but not TLR2 ligand-induced shock, an outcome that correlates with enhanced proinflammatory cytokine production in vitro and in vivo. Further analysis revealed that LPS-stimulated LRG47-deficient macrophages display enhanced phosphorylation of p38, a downstream response associated with TLR4/MyD88 rather than IFN-beta/STAT-1 signaling. In contrast, LPS-induced phosphorylation of IFN regulatory factor-3 and expression of IFN-beta or the type I IFN-regulated genes, CCL5 and CCL10, were unaltered in LRG47(-/-) cells. Together, these observations indicate that in LPS-stimulated murine macrophages LRG47 is induced by IFN-beta and negatively regulates TLR4 signaling to prevent excess proinflammatory cytokine production and shock. Thus, our findings reveal a new host-protective function for this GTPase in the response to pathogenic encounter.
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页码:5514 / 5522
页数:9
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