title: Cell adhesion molecules regulate fibrotic process via Th1/Th2/Th17 cell balance in a bleomycin-induced scleroderma model.
abstract: Mice s.c. injected with bleomycin, an experimental model for human systemic sclerosis, develop skin and lung fibrosis, which is mediated by inflammatory cell infiltration. This process is highly regulated by multiple adhesion molecules and does not require Ag sensitization. To assess the role of adhesion molecules in this pathogenetic process, bleomycin-induced fibrosis was examined in mice lacking adhesion molecules. L-selectin and/or ICAM-1 deficiency inhibited skin and lung fibrosis with decreased Th2 and Th17 cytokines and increased Th1 cytokines. In contrast, P-selectin deficiency, E-selectin deficiency with or without P-selectin blockade, or P-selectin glycoprotein ligand 1 (PSGL-1) deficiency augmented the fibrosis in parallel with increased Th2 and Th17 cytokines and decreased Th1 cytokines. Furthermore, loss of L-selectin and/or ICAM-1 reduced Th2 and Th17 cell numbers in bronchoalveolar lavage fluid, whereas loss of P-selectin, E-selectin, or PSGL-1 reduced Th1 cell numbers. Moreover, Th1 cells exhibited higher PSGL-1 expression and lower expression of LFA-1, a ligand for ICAM-1, whereas Th2 and Th17 cells showed higher LFA-1 and lower PSGL-1 expression. This study suggests that L-selectin and ICAM-1 regulate Th2 and Th17 cell accumulation into the skin and lung, leading to the development of fibrosis, and that P-selectin, E-selectin, and PSGL-1 regulate Th1 cell infiltration, resulting in the inhibition of fibrosis.
authors.affiliation: Department of Dermatology, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan.
authors.forename: Ayumi
authors.initials: A
authors.lastname: Yoshizaki
authors.forename: Koichi
authors.initials: K
authors.lastname: Yanaba
authors.forename: Yohei
authors.initials: Y
authors.lastname: Iwata
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Komura
authors.forename: Asako
authors.initials: A
authors.lastname: Ogawa
authors.forename: Yuichiro
authors.initials: Y
authors.lastname: Akiyama
authors.forename: Eiji
authors.initials: E
authors.lastname: Muroi
authors.forename: Toshihide
authors.initials: T
authors.lastname: Hara
authors.forename: Fumihide
authors.initials: F
authors.lastname: Ogawa
authors.forename: Motoi
authors.initials: M
authors.lastname: Takenaka
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Shimizu
authors.forename: Minoru
authors.initials: M
authors.lastname: Hasegawa
authors.forename: Manabu
authors.initials: M
authors.lastname: Fujimoto
authors.forename: Thomas F
authors.initials: TF
authors.lastname: Tedder
authors.forename: Shinichi
authors.initials: S
authors.lastname: Sato
mesh_terms: D000818:Animals; D001761:Bleomycin; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D019040:E-Selectin / Q000235:genetics / Q000378:metabolism; D005260:Female; D005347:Fibroblasts / Q000276:immunology / Q000378:metabolism; D005355:Fibrosis / Q000276:immunology; D005434:Flow Cytometry; D018799:Intercellular Adhesion Molecule-1 / Q000235:genetics / Q000276:immunology*; D020381:Interleukin-17 / Q000276:immunology / Q000378:metabolism; D019041:L-Selectin / Q000235:genetics / Q000276:immunology*; D008297:Male; D008562:Membrane Glycoproteins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D019007:P-Selectin / Q000235:genetics / Q000378:metabolism; D011658:Pulmonary Fibrosis / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012595:Scleroderma, Systemic / Q000139:chemically induced / Q000235:genetics / Q000276:immunology*; D012867:Skin / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D006377:T-Lymphocytes, Helper-Inducer / Q000276:immunology* / Q000378:metabolism; D018417:Th1 Cells / Q000276:immunology / Q000378:metabolism; D018418:Th2 Cells / Q000276:immunology / Q000378:metabolism
chemical_list: D016207:Cytokines; D019040:E-Selectin; D020381:Interleukin-17; D008562:Membrane Glycoproteins; D019007:P-Selectin; C084882:P-selectin ligand protein; D001761:Bleomycin; D018799:Intercellular Adhesion Molecule-1; D019041:L-Selectin