Cooperation of TLR2 with MyD88, PI3K, and Rac1 in lipoteichoic acid-induced cPLA2/COX-2-dependent airway inflammatory responses

I-Ta Lee, Chiang Wen Lee, Wei Hsuan Tung, Shyi Wu Wang, Chih Chung Lin, Jwu Ching Shu, Chuen Mao Yang

研究成果: 雜誌貢獻文章同行評審

71 引文 斯高帕斯(Scopus)

摘要

Lipoteichoic acid (LTA) plays a role in the pathogenesis of severe inflammatory responses induced by Grampositive bacterial infection. Cytosolic phospholipase A2 (cPLA2), cyclooxygenase-2 (COX-2), prostaglandin E2 (PGE2), and interleukin (IL)-6 have been demonstrated to engage in airway inflammation. In this study, LTA-induced cPLA2 and COX-2 expression and PGE2 or IL-6 synthesis were attenuated by transfection with siRNAs of TLR2, MyD88, Akt, p42, p38, JNK2, and p65 or pretreatment with the inhibitors of PI3K (LY294002), p38 (SB202190), MEK1/2 (U0126), JNK1/2 (SP600125), and NF-κB (helenalin) in human tracheal smooth muscle cells (HTSMCs). LTA also induced cPLA2 and COX-2 expression and leukocyte count in bronchoalveolar lavage fluid in mice. LTA-regulated PGE2 or IL-6 production was inhibited by pretreatment with the inhibitors of cPLA2 (AACOCF3) and COX-2 (NS-398) or transfection with cPLA2 siRNA or COX-2 siRNA, respectively. LTA-stimulated NF-κB translocation or cPLA2 phosphorylation was attenuated by pretreatment with LY294002, SB202190, U0126, or SP600125. Furthermore, LTA could stimulate TLR2, MyD88, PI3K, and Rac1 complex formation. We also demonstrated that Staphylococcus aureus could trigger these responses through a similar signaling cascade in HTSMCs. It was found that PGE2 could directly stimulate IL-6 production in HTSMCs or leukocyte count in bronchoalveolar lavage fluid in mice. These results demonstrate that LTA-induced MAPKs activation is mediated through the TLR2/MyD88/PI3K/Rac1/Akt pathway, which in turn initiates the activation of NF-κB, and ultimately induces cPLA2/COX-2- dependent PGE2 and IL-6 generation.
原文英語
頁(從 - 到)1671-1684
頁數14
期刊American Journal of Pathology
176
發行號4
DOIs
出版狀態已發佈 - 一月 1 2010
對外發佈

ASJC Scopus subject areas

  • 病理學與法醫學

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