Abstract
Bacterial lipopolysaccharide (LPS) triggers innate immune responses through Toll-like receptor (TLR) 4. We show here that the suppressor of cytokine-signaling-1 (SOCS1/JAB) is rapidly induced by LPS and negatively regulates LPS signaling. SOCS1(+/-) mice or SOCS1(-/-) mice with interferon-gamma (IFNgamma)-deficient background were more sensitive to LPS-induced lethal effects than were wild-type littermates. LPS-induced NO(2)(-) synthesis and TNFalpha production were augmented in SOCS1(-/-) macrophages. Furthermore, LPS tolerance, a protection mechanism against endotoxin shock, was also strikingly reduced in SOCS1(-/-) cells. LPS-induced I-kappaB and p38 phosphorylation was upregulated in SOCS1(-/-) macrophages, and forced expression of SOCS1 suppressed LPS-induced NF-kappaB activation. Thus, SOCS1 directly suppresses TLR4 signaling and modulates innate immunity.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Carrier Proteins / physiology*
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Cells, Cultured
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Drosophila Proteins*
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Lipopolysaccharides / pharmacology
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Macrophage Activation / drug effects
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Macrophage Activation / physiology*
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Macrophages, Peritoneal / physiology*
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Membrane Glycoproteins / physiology
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Mice
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Mice, Inbred C57BL
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NF-kappa B / physiology
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Phosphorylation
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Receptors, Cell Surface / physiology
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Repressor Proteins*
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Signal Transduction / drug effects
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Signal Transduction / physiology
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Suppressor of Cytokine Signaling 1 Protein
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Suppressor of Cytokine Signaling Proteins
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Toll-Like Receptor 4
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Toll-Like Receptors
Substances
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Carrier Proteins
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Drosophila Proteins
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Lipopolysaccharides
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Membrane Glycoproteins
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NF-kappa B
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Receptors, Cell Surface
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Repressor Proteins
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Socs1 protein, mouse
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Suppressor of Cytokine Signaling 1 Protein
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Suppressor of Cytokine Signaling Proteins
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Toll-Like Receptor 4
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Toll-Like Receptors