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J. Biol. Chem., Vol. 280, Issue 47, 38969-38975, November 25, 2005

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Toll-like Receptor 4 Signaling Regulates Cytosolic Phospholipase A₂ Activation and Lipid Generation in Lipopolysaccharide-stimulated Macrophages^*

From the Critical Care Medicine Department, Clinical Center, National Institutes of Health, Bethesda, Maryland 20892

Inflammatory lipid mediators such as prostaglandins and leukotrienes play crucial roles in the pathogenesis of bacterial lipopolysaccharide (LPS)-induced inflammation. Cytosolic phospholipase A₂ (cPLA₂) is a key enzyme in the generation of pro-inflammatory lipid mediators. Here, we found that Toll-like receptor 4 (TLR4) is essential for LPS-induced cPLA₂ activation and lipid release. Inhibition of TLR4 protein expression by TLR4 small interfering RNA or neutralization of TLR4 by the specific antibody against TLR4/MD2 blocked cPLA₂ phosphorylation and cPLA₂-hydrolyzed arachidonic acid release. Furthermore, activation of the TLR4 signaling pathway by LPS regulated cPLA₂ activation and lipid release. cPLA₂ phosphorylation and cPLA₂-hydrolyzed lipid release were significantly impaired when TLR4 adaptor protein, either MyD88 or TRIF, was knocked down in LPS-stimulated macrophages. Similarly, LPS-induced arachidonate release was inhibited in cells transfected with a dominant-negative MyD88 or TRIF construct. Subsequently, cPLA₂ activation could be suppressed by inhibition of the TLR4 adaptor protein-directed p38 and ERK MAPK pathways. These findings suggest that, in LPS-induced inflammation, the TLR4-mediated MyD88- and TRIF-dependent MAPK pathways result in cPLA₂ activation and production of pro-inflammatory lipid mediators.

Received for publication, August 24, 2005 , and in revised form, September 19, 2005.

^* The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ To whom correspondence should be addressed: Critical Care Medicine Dept., Clinical Center, NIH, Bldg. 10, Rm. 7-D-43, Bethesda, MD 20892. Tel.: 301-496-9320; Fax: 301-402-1213; E-mail: jshelhamer{at}nih.gov.

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