title: Plasminogen activator inhibitor-1 regulates LPS-induced TLR4/MD-2 pathway activation and inflammation in alveolar macrophages.
abstract: Toll-like receptor 4 (TLR4) and myeloid differentiation protein 2 (MD-2) are the main lipopolysaccharide (LPS) binding receptors that respond to inflammatory stimuli and mediate NF-kappa B (NF-κB) signaling pathway in macrophages. We have previously shown that plasminogen activator inhibitor-1 (PAI-1) deletion increased lung injury induced by intratracheal instillation of LPS through downregulation of TLR4 negative regulators. However, the mechanisms by which PAI-1 regulates lung inflammation are largely unknown. The aim of this study is to assess the relationship between PAI-1 and TLR4 signaling pathways in LPS-induced NR8383 cells inflammatory reaction. The results showed that the levels of PAI-1, TNF-α, and IL-1β protein were increased remarkably in NR8383 cell supernatants after LPS stimulation. PAI-1 gene knockdown reduced TNF-α and IL-1β levels in cell supernatants and inhibited the NF-κB p65 protein expression in NR8383 cells. The upregulated mRNA and protein expressions of TLR4, MD-2, and myeloid differentiation protein (MyD88) induced by LPS were attenuated after PAI-1 gene knockdown. Conversely, overexpression of PAI-1 in NR8383 cells not only resulted in additional mRNA and protein production of PAI-1, TLR4, MD-2, and MyD88, it also aggravated the inflammatory response induced by LPS. In conclusion, PAI-1 contributes to the regulation of LPS-induced inflammatory response in NR8383 cells, likely by affecting the TLR4-MD-2/NF-κB signaling transduction pathway.
authors.affiliation: Department of Geriatrics, Zhongshan Hospital, Fudan University, 180 Fenglin Road, Shanghai, China.
authors.forename: Weiying
authors.initials: W
authors.lastname: Ren
authors.forename: Zhonghui
authors.initials: Z
authors.lastname: Wang
authors.forename: Feng
authors.initials: F
authors.lastname: Hua
authors.forename: Lei
authors.initials: L
authors.lastname: Zhu
mesh_terms: D000818:Animals; D002460:Cell Line; D004305:Dose-Response Relationship, Drug; D055785:Gene Knockdown Techniques; D007249:Inflammation / Q000139:chemically induced / Q000378:metabolism; D008070:Lipopolysaccharides / Q000633:toxicity*; D051218:Lymphocyte Antigen 96 / Q000378:metabolism*; D016676:Macrophages, Alveolar / Q000187:drug effects / Q000378:metabolism*; D017395:Plasminogen Activator Inhibitor 1 / Q000502:physiology*; D051381:Rats; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D051197:Toll-Like Receptor 4 / Q000378:metabolism*
chemical_list: D008070:Lipopolysaccharides; C411728:Ly96 protein, mouse; D051218:Lymphocyte Antigen 96; D017395:Plasminogen Activator Inhibitor 1; C495347:Tlr4 protein, rat; D051197:Toll-Like Receptor 4