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Proc Natl Acad Sci U S A. 2006 Sep 12;103(37):13777-82. Epub 2006 Sep 5.

LPS-induced TNF-alpha factor (LITAF)-deficient mice express reduced LPS-induced cytokine: Evidence for LITAF-dependent LPS signaling pathways.

Author information

  • 1Department of Periodontology, Boston University Medical Center, Boston University, Boston, MA 02118, USA.

Erratum in

  • Proc Natl Acad Sci U S A. 2007 Feb 20;104(8):3015.

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.

PMID:
16954198
[PubMed - indexed for MEDLINE]
PMCID:
PMC1560089
Free PMC Article

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