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PMID:16954198

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Citation

Tang, X, Metzger, D, Leeman, S and Amar, S (2006) LPS-induced TNF-alpha factor (LITAF)-deficient mice express reduced LPS-induced cytokine: Evidence for LITAF-dependent LPS signaling pathways. Proc. Natl. Acad. Sci. U.S.A. 103:13777-82

Abstract

Previously we identified a transcription factor, LPS-Induced TNF-alpha Factor (LITAF), mediating inflammatory cytokine expression in LPS-induced processes. To characterize the role of LITAF in vivo, we generated a macrophage-specific LITAF-deficient mouse (macLITAF(-/-)). Our data demonstrate that in macrophages (i) several cytokines (such as TNF-alpha, IL-6, sTNF-RII, and CXCL16) are induced at lower levels in macLITAF(-/-) compared with LITAF(+/+) control macrophages; (ii) macLITAF(-/-) mice are more resistant to LPS-induced lethality. To further identify LITAF signaling pathways, we tested mouse TLR-2(-/-), -4(-/-), and -9(-/-) and WT peritoneal macrophages exposed to LPS. Using these cells, we now show that LITAF expression can be induced after challenge either with LPS from Porphyromonas gingivalis via agonism at TLR-2, or with LPS from Escherichia coli via agonism at TLR-4, both requiring functional MyD88. We also show that, in response to LPS, the MyD88-dependent LITAF pathway differs from the NF-kappaB pathway. Furthermore, using a kinase array, p38alpha was found to mediate LITAF phosphorylation and the inhibition of p38alpha with a p38-specific inhibitor (SB203580) blocked LITAF nuclear translocation and reduced LPS-induced TNF-alpha protein levels. Finally, macLITAF(-/-) macrophages rescued by LITAF cDNA transfection restored levels of TNF-alpha similar to those observed in WT cells. We conclude that LITAF is an important mediator of the LPS-induced inflammatory response that can be distinguished from NF-kappaB pathway and that p38alpha is the specific kinase involved in the pathway linking LPS/MyD88/LITAF to TNF.

Links

PubMed PMC1560089 Online version:10.1073/pnas.0605988103

Keywords

Adaptor Proteins, Signal Transducing/metabolism; Animals; Cytokines/metabolism; Down-Regulation; Escherichia coli/immunology; Lipopolysaccharides/toxicity; Macrophages/immunology; Mice; Mice, Mutant Strains; Myeloid Differentiation Factor 88; NF-kappa B/metabolism; Nuclear Proteins/deficiency; Nuclear Proteins/genetics; Nuclear Proteins/physiology; Phosphorylation; Porphyromonas gingivalis/immunology; Protein Transport; Shock, Septic/genetics; Shock, Septic/immunology; Signal Transduction; Toll-Like Receptors/metabolism; Transcription Factors/deficiency; Transcription Factors/genetics; Transcription Factors/physiology; Tumor Necrosis Factor-alpha/metabolism; p38 Mitogen-Activated Protein Kinases/metabolism

Significance

Annotations

Gene product Qualifier GO Term Evidence Code with/from Aspect Extension Notes Status

MOUSE:LITAF

acts_upstream_of_or_within

GO:0001817: regulation of cytokine production

ECO:0000315: mutant phenotype evidence used in manual assertion

MGI:MGI:3687962

P

  • regulates_o_occurs_in:(CL:0000235)

Seeded From UniProt

complete

MOUSE:LITAF

acts_upstream_of_or_within

GO:0071222: cellular response to lipopolysaccharide

ECO:0000315: mutant phenotype evidence used in manual assertion

MGI:MGI:3687962

P

Seeded From UniProt

complete

MOUSE:LITAF

acts_upstream_of_or_within

GO:0001817: regulation of cytokine production

ECO:0000315: mutant phenotype evidence used in manual assertion

MGI:MGI:3687962

P

Seeded From UniProt

complete

MOUSE:MK14

acts_upstream_of_or_within

GO:0042307: positive regulation of protein import into nucleus

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete


See also

References

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