title: IL-13-induced chemokine responses in the lung: role of CCR2 in the pathogenesis of IL-13-induced inflammation and remodeling.
abstract: IL-13 stimulates inflammatory and remodeling responses and contributes to the pathogenesis of human airways disorders. To further understand the cellular and molecular events that mediate these responses, we characterized the effects of IL-13 on monocyte chemotactic proteins (MCPs) and compared the tissue effects of transgenic IL-13 in mice with wild-type (+/+) and null (-/-) CCR2 loci. Transgenic IL-13 was a potent stimulator of MCP-1, -2, -3, and -5. This stimulation was not specific for MCPs because macrophage-inflammatory protein (MIP)-1alpha, MIP-1beta, MIP-2, MIP-3alpha, thymus- and activation-regulated chemokine, thymus-expressed chemokine, eotaxin, eotaxin 2, macrophage-derived chemokines, and C10 were also induced. The ability of IL-13 to increase lung size, alveolar size, and lung compliance, to stimulate pulmonary inflammation, hyaluronic acid accumulation, and tissue fibrosis, and to cause respiratory failure and death were markedly decreased, whereas mucus metaplasia was not altered in CCR2(-/-) mice. CCR2 deficiency did not decrease the basal or IL-13-stimulated expression of target matrix metalloproteinases or cathepsins but did increase the levels of mRNA encoding alpha1-antitrypsin, tissue inhibitor of metalloproteinase-1, -2, and -4, and secretory leukocyte proteinase inhibitor. In addition, the levels of bioactive and total TGF-beta(1) were decreased in lavage fluids from IL-13 transgenic mice with -/- CCR2 loci. These studies demonstrate that IL-13 is a potent stimulator of MCPs and other CC chemokines and document the importance of MCP-CCR2 signaling in the pathogenesis of the IL-13-induced pulmonary phenotype.
authors.affiliation: Section of Pulmonary and Critical Care Medicine, Departments of Internal Medicine and Pathology, Yale University School of Medicine, New Haven, CT 06520, USA.
authors.forename: Zhou
authors.initials: Z
authors.lastname: Zhu
authors.forename: Bing
authors.initials: B
authors.lastname: Ma
authors.forename: Tao
authors.initials: T
authors.lastname: Zheng
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Homer
authors.forename: Chun Geun
authors.initials: CG
authors.lastname: Lee
authors.forename: Israel F
authors.initials: IF
authors.lastname: Charo
authors.forename: Paul
authors.initials: P
authors.lastname: Noble
authors.forename: Jack A
authors.initials: JA
authors.lastname: Elias
mesh_terms: D000818:Animals; D001992:Bronchoalveolar Lavage Fluid / Q000737:chemistry / Q000276:immunology; D002478:Cells, Cultured; D018932:Chemokine CCL2 / Q000378:metabolism; D019742:Chemokines, CC / Q000096:biosynthesis / Q000235:genetics; D010450:Endopeptidases / Q000096:biosynthesis; D006820:Hyaluronic Acid / Q000378:metabolism; D007249:Inflammation / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D018793:Interleukin-13 / Q000009:adverse effects* / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D008168:Lung / Q000201:enzymology / Q000276:immunology* / Q000378:metabolism / Q000473:pathology*; D008170:Lung Compliance; D008679:Metaplasia / Q000276:immunology / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D008907:Mink; D009093:Mucus / Q000166:cytology / Q000276:immunology; D010641:Phenotype; D011480:Protease Inhibitors / Q000378:metabolism; D011650:Pulmonary Alveoli / Q000473:pathology; D011658:Pulmonary Fibrosis / Q000235:genetics / Q000276:immunology* / Q000378:metabolism / Q000473:pathology*; D012333:RNA, Messenger / Q000096:biosynthesis; D054390:Receptors, CCR2; D019707:Receptors, Chemokine / Q000096:biosynthesis / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D012131:Respiratory Insufficiency / Q000276:immunology / Q000473:pathology; D020545:Respiratory Mucosa / Q000276:immunology / Q000378:metabolism; D014109:Total Lung Capacity; D016212:Transforming Growth Factor beta / Q000096:biosynthesis; D053773:Transforming Growth Factor beta1
chemical_list: C515334:CCR2 protein, human; C515335:Ccr2 protein, mouse; D018932:Chemokine CCL2; D019742:Chemokines, CC; D018793:Interleukin-13; D011480:Protease Inhibitors; D012333:RNA, Messenger; D054390:Receptors, CCR2; D019707:Receptors, Chemokine; C508960:TGFB1 protein, human; C508961:Tgfb1 protein, mouse; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1; D006820:Hyaluronic Acid; D010450:Endopeptidases