title: TLR2-mediated production of IL-27 and chemokines by respiratory epithelial cells promotes bleomycin-induced pulmonary fibrosis in mice.
abstract: Idiopathic pulmonary fibrosis is a fatal disease characterized by progressive destruction of the lung. Although TLR2 bridges innate and adaptive immunity by sensing tissue damage, its role in pulmonary fibrosis remains unclear. To address this issue, TLR2(-/-) and WT mice were examined for bleomycin-induced pulmonary fibrosis (BIPF). Flow cytometric and immunohistochemical analysis revealed that TLR2 expression in bronchial epithelial and immune cells of the lungs was upregulated in WT mice during BIPF. Levels of IL-27, TGF-β, chemokines, and hydroxyproline were lower in lungs of TLR2(-/-) mice than in those of WT mice, but IL-17 levels were higher in TLR2(-/-) mice. In in vivo experiments using bone marrow-chimeric mice, TLR2 expression on respiratory epithelial cells, rather than immune cells, induced IL-27 and chemokine production in the lungs, further stimulating BIPF. This effect of TLR2 depended on IRF complexes and MyD88. BIPF was more severe in IL-17A(-/-) mice and in TLR2(-/-) mice treated with anti-IL-17 mAb than in TLR2(-/-) and WT mice. Furthermore, IL-27 blockade in WT mice reduced hydroxyproline levels by enhancing IL-17 production, whereas the treatment of TLR2(-/-) mice with a chemokine mixture increased hydroxyproline levels by recruiting inflammatory cells into the lungs. TLR2 signaling promotes BIPF by inducing IL-27 and chemokine production by respiratory epithelial cells, thereby inhibiting IL-17 production and recruiting inflammatory cells into the lungs.
authors.affiliation: Department of Pathology, Seoul National University College of Medicine, Seoul 110-799, Korea.
authors.forename: Hye Sung
authors.initials: HS
authors.lastname: Kim
authors.forename: Heounjeong
authors.initials: H
authors.lastname: Go
authors.forename: Shizuo
authors.initials: S
authors.lastname: Akira
authors.forename: Doo Hyun
authors.initials: DH
authors.lastname: Chung
mesh_terms: D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000633:toxicity; D001761:Bleomycin / Q000633:toxicity; D015153:Blotting, Western; D018893:Bronchoalveolar Lavage; D002469:Cell Separation; D018925:Chemokines / Q000096:biosynthesis; D004195:Disease Models, Animal; D004797:Enzyme-Linked Immunosorbent Assay; D005434:Flow Cytometry; D054990:Idiopathic Pulmonary Fibrosis / Q000139:chemically induced / Q000276:immunology* / Q000378:metabolism; D007150:Immunohistochemistry; D020381:Interleukin-17 / Q000276:immunology* / Q000378:metabolism; D007378:Interleukins / Q000276:immunology* / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D020545:Respiratory Mucosa / Q000276:immunology* / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000276:immunology; D051195:Toll-Like Receptor 2 / Q000276:immunology* / Q000378:metabolism
chemical_list: D000903:Antibiotics, Antineoplastic; D018925:Chemokines; C486767:Il27 protein, mouse; D020381:Interleukin-17; D007378:Interleukins; C493486:Tlr2 protein, mouse; D051195:Toll-Like Receptor 2; D001761:Bleomycin