title: TLR4 signaling induces TLR3 up-regulation in alveolar macrophages during acute lung injury.
abstract: Acute lung injury is a life-threatening inflammatory response caused by severe infection. Toll-like receptors in alveolar macrophages (AMΦ) recognize the molecular constituents of pathogens and activate the host's innate immune responses. Numerous studies have documented the importance of TLR-TLR cross talk, but few studies have specifically addressed the relationship between TLR4 and TLR3. We explored a novel mechanism of TLR3 up-regulation that is induced by LPS-TLR4 signaling in a dose- and time-dependent manner in AMΦ from C57BL/6 mice, while the LPS-induced TLR3 expression was significantly reduced in TLR4-/-and Myd88-/-mice and following pretreatment with a NF-κB inhibitor. The enhanced TLR3 up-regulation in AMΦ augmented the expression of cytokines and chemokines in response to sequential challenges with LPS and Poly I:C, a TLR3 ligand, which was physiologically associated with amplified AMΦ-induced PMN migration into lung alveoli. Our study demonstrates that the synergistic effect between TLR4 and TLR3 in macrophages is an important determinant in acute lung injury and, more importantly, that TLR3 up-regulation is dependent on TLR4-MyD88-NF-κB signaling. These results raise the possibility that bacterial infections can induce sensitivity to viral infections, which may have important implications for the therapeutic manipulation of the innate immune system.
authors.affiliation: Department of Anesthesiology, East Hospital, Tongji University School of Medicine, Shanghai, China.
authors.forename: Xibing
authors.initials: X
authors.lastname: Ding
authors.affiliation: Department of Anesthesiology, East Hospital, Tongji University School of Medicine, Shanghai, China.
authors.forename: Shuqing
authors.initials: S
authors.lastname: Jin
authors.affiliation: Department of Anesthesiology, East Hospital, Tongji University School of Medicine, Shanghai, China.
authors.forename: Yao
authors.initials: Y
authors.lastname: Tong
authors.affiliation: Department of Anesthesiology, East Hospital, Tongji University School of Medicine, Shanghai, China.
authors.forename: Xi
authors.initials: X
authors.lastname: Jiang
authors.affiliation: Department of Anesthesiology, East Hospital, Tongji University School of Medicine, Shanghai, China.
authors.forename: Zhixia
authors.initials: Z
authors.lastname: Chen
authors.affiliation: Department of Anesthesiology, East Hospital, Tongji University School of Medicine, Shanghai, China.
authors.forename: Shuya
authors.initials: S
authors.lastname: Mei
authors.affiliation: Department of Anesthesiology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
authors.forename: Liming
authors.initials: L
authors.lastname: Zhang
authors.affiliation: Department of Surgery, University of Pittsburgh School of Medicine, 200 Lothrop St, Pittsburgh, PA 15213, USA.
authors.forename: Timothy R
authors.initials: TR
authors.lastname: Billiar
authors.affiliation: Department of Anesthesiology, East Hospital, Tongji University School of Medicine, Shanghai, China.
authors.forename: Quan
authors.initials: Q
authors.lastname: Li
mesh_terms: D055371:Acute Lung Injury / Q000473:pathology*; D000818:Animals; D002478:Cells, Cultured; D004306:Dose-Response Relationship, Immunologic; D007113:Immunity, Innate; D008070:Lipopolysaccharides / Q000276:immunology; D016676:Macrophages, Alveolar / Q000276:immunology*; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D053594:Myeloid Differentiation Factor 88 / Q000172:deficiency / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism*; D015398:Signal Transduction; D051196:Toll-Like Receptor 3 / Q000378:metabolism*; D051197:Toll-Like Receptor 4 / Q000172:deficiency / Q000378:metabolism*; D015854:Up-Regulation
chemical_list: D008070:Lipopolysaccharides; C507780:Myd88 protein, mouse; D053594:Myeloid Differentiation Factor 88; D016328:NF-kappa B; C519703:TLR3 protein, mouse; C493487:Tlr4 protein, mouse; D051196:Toll-Like Receptor 3; D051197:Toll-Like Receptor 4