Cooperation of TLR2 with MyD88, PI3K, and Rac1 in Lipoteichoic Acid–Induced cPLA2/COX-2–Dependent Airway Inflammatory Responses
| Autor: | Chuen-Mao Yang, Wei Hsuan Tung, Chiang-Wen Lee, I-Ta Lee, Shyi-Wu Wang, Jwu Ching Shu, Chih-Chung Lin |
|---|---|
| Rok vydání: | 2010 |
| Předmět: |
Lipopolysaccharides
Male rac1 GTP-Binding Protein Staphylococcus aureus Small interfering RNA Myocytes Smooth Muscle Inflammation Pathology and Forensic Medicine Mice Phosphatidylinositol 3-Kinases chemistry.chemical_compound Phospholipase A2 Leukocytes medicine Animals Humans Prostaglandin E2 Protein kinase B PI3K/AKT/mTOR pathway biology Interleukin-6 Group IV Phospholipases A2 respiratory system Molecular biology Toll-Like Receptor 2 Teichoic Acids Trachea chemistry Cyclooxygenase 2 Myeloid Differentiation Factor 88 Immunology biology.protein lipids (amino acids peptides and proteins) Lipoteichoic acid medicine.symptom Regular Articles Helenalin medicine.drug |
| Zdroj: | The American Journal of Pathology. 176:1671-1684 |
| ISSN: | 0002-9440 |
| DOI: | 10.2353/ajpath.2010.090714 |
| Popis: | Lipoteichoic acid (LTA) plays a role in the pathogenesis of severe inflammatory responses induced by Gram-positive bacterial infection. Cytosolic phospholipase A(2) (cPLA(2)), cyclooxygenase-2 (COX-2), prostaglandin E(2) (PGE(2)), and interleukin (IL)-6 have been demonstrated to engage in airway inflammation. In this study, LTA-induced cPLA(2) and COX-2 expression and PGE(2) 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-kappaB (helenalin) in human tracheal smooth muscle cells (HTSMCs). LTA also induced cPLA(2) and COX-2 expression and leukocyte count in bronchoalveolar lavage fluid in mice. LTA-regulated PGE(2) or IL-6 production was inhibited by pretreatment with the inhibitors of cPLA(2) (AACOCF(3)) and COX-2 (NS-398) or transfection with cPLA(2) siRNA or COX-2 siRNA, respectively. LTA-stimulated NF-kappaB translocation or cPLA(2) 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 PGE(2) 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-kappaB, and ultimately induces cPLA(2)/COX-2-dependent PGE(2) and IL-6 generation. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|