title: Interleukin-33 potentiates bleomycin-induced lung injury.
abstract: The mechanisms of interstitial lung disease (ILD) remain incompletely understood, although recent observations have suggested an important contribution by IL-33. Substantial elevations in IL-33 expression were found in the lungs of patients with idiopathic pulmonary fibrosis and scleroderma lung disease, as well as in the bleomycin injury mouse model. Most of the observed IL-33 expression was intracellular and intranuclear, suggesting involvement of the full-length (fl) protein, but not of the proteolytically processed mature IL-33 cytokine. The effects of flIL-33 on mouse lungs were assessed independently and in combination with bleomycin injury, using recombinant adenovirus-mediated gene delivery. Bleomycin-induced changes were not affected by gene deficiency of the IL-33 receptor T1/ST2. Combined flIL-33 expression and bleomycin injury exerted a synergistic effect on pulmonary lymphocyte and collagen accumulation, which could be explained by synergistic regulation of the cytokines transforming growth factor-β, IL-6, monocyte chemotactic protein-1, macrophage inflammatory protein\x{2013}1α, and tumor necrosis factor-α. By contrast, no increase in the levels of the Th2 cytokines IL-4, IL-5, or IL-13 was evident. Moreover, flIL-33 was found to increase the expression of several heat shock proteins (HSPs) significantly, and in particular HSP70, which is known to be associated with ILD. Thus, flIL-33 is a synergistic proinflammatory and profibrotic regulator that acts by stimulating the expression of several non-Th2 cytokines, and activates the expression of HSP70.
authors.affiliation: 1 Division of Rheumatology and Clinical Immunology, Department of Medicine, University of Maryland School of Medicine, Baltimore; and.
authors.forename: Irina G
authors.initials: IG
authors.lastname: Luzina
authors.forename: Pavel
authors.initials: P
authors.lastname: Kopach
authors.forename: Virginia
authors.initials: V
authors.lastname: Lockatell
authors.forename: Phillip H
authors.initials: PH
authors.lastname: Kang
authors.forename: Ashish
authors.initials: A
authors.lastname: Nagarsekar
authors.forename: Allen P
authors.initials: AP
authors.lastname: Burke
authors.forename: Jeffrey D
authors.initials: JD
authors.lastname: Hasday
authors.forename: Nevins W
authors.initials: NW
authors.lastname: Todd
authors.forename: Sergei P
authors.initials: SP
authors.lastname: Atamas
mesh_terms: D000818:Animals; D001761:Bleomycin / Q000633:toxicity*; D016207:Cytokines / Q000276:immunology; D004195:Disease Models, Animal; D005260:Female; D015870:Gene Expression; D018840:HSP70 Heat-Shock Proteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D018836:Inflammation Mediators / Q000276:immunology / Q000378:metabolism; D000072179:Interleukin-1 Receptor-Like 1 Protein; D000067596:Interleukin-33; D007378:Interleukins / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D008168:Lung / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D017563:Lung Diseases, Interstitial / Q000209:etiology / Q000276:immunology / Q000473:pathology; D055370:Lung Injury / Q000209:etiology* / Q000276:immunology / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D011499:Protein Processing, Post-Translational; D018123:Receptors, Interleukin / Q000172:deficiency / Q000235:genetics / Q000276:immunology
chemical_list: D016207:Cytokines; D018840:HSP70 Heat-Shock Proteins; C486189:Il1rl1 protein, mouse; C506535:Il33 protein, mouse; D018836:Inflammation Mediators; D000072179:Interleukin-1 Receptor-Like 1 Protein; D000067596:Interleukin-33; D007378:Interleukins; D018123:Receptors, Interleukin; D001761:Bleomycin