4.5 Article

The induction of macrophage gene expression by LPS predominantly utilizes Myd88-dindependent signaling cascades

期刊

PHYSIOLOGICAL GENOMICS
卷 19, 期 3, 页码 319-330

出版社

AMER PHYSIOLOGICAL SOC
DOI: 10.1152/physiolgenomics.00128.2004

关键词

monocytes/macrophages; lipopolysaccharide; gene regulation; signal transduction; cellular activation

资金

  1. NCRR NIH HHS [RR-14466] Funding Source: Medline
  2. NHLBI NIH HHS [HL-66678, HL-45098] Funding Source: Medline
  3. NIDDK NIH HHS [DK-50305] Funding Source: Medline
  4. NIGMS NIH HHS [GM-54060] Funding Source: Medline

向作者/读者索取更多资源

Myeloid differentiation protein-88 (MyD88) is a signal adaptor protein required for cytokine production following engagement of Toll-like receptors (TLRs) by their cognate ligands. Activation of both TLR-3 and TLR-4, however, can engage signaling events independent of MyD88 expression. The relative importance of these MyD88-dependent and - independent signaling pathways in the macrophage response to lipopolysaccharide (LPS) is unknown. Here we define these events using microarray expression profiling of LPS-stimulated macrophages taken from MyD88-null and wild-type mice. Of the 1,055 genes found to be LPS responsive, only 21.5% were dependent on MyD88 expression, with MyD88-independent genes constituting 74.7% of the genetic response. This MyD88-independent gene expression was predominantly transcriptionally regulated, as it was unaffected by cycloheximide blockade of new protein synthesis. A previously undescribed group of LPS-regulated genes (3.8%), whose induction or repression was significantly greater in the absence of MyD88, was also identified by these studies. The regulation of these genes suggested that MyD88 could serve as a molecular brake, constraining gene activity in a subset of LPS-responsive genes. The findings generated with LPS stimulation were recapitulated by exposure of macrophages to live Escherichia coli. These expression-profiling studies redefine the current dogma of TLR-4 signaling and establish that MyD88, although essential for some of the best-characterized macrophage responses to LPS, is not required for the regulation of the majority of genes engaged by macrophage exposure to endotoxin or live bacteria.

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