title: Role of CCR5 in IFN-gamma-induced and cigarette smoke-induced emphysema.
abstract: Th1 inflammation and remodeling characterized by tissue destruction frequently coexist in human diseases. To further understand the mechanisms of these responses, we defined the role(s) of CCR5 in the pathogenesis of IFN-gamma-induced inflammation and remodeling in a murine emphysema model. IFN-gamma was a potent stimulator of the CCR5 ligands macrophage inflammatory protein-1alpha/CCL-3 (MIP-1alpha/CCL-3), MIP-1beta/CCL-4, and RANTES/CCL-5, among others. Antibody neutralization or null mutation of CCR5 decreased IFN-gamma-induced inflammation, DNA injury, apoptosis, and alveolar remodeling. These interventions decreased the expression of select chemokines, including CCR5 ligands and MMP-9, and increased levels of secretory leukocyte protease inhibitor. They also decreased the expression and/or activation of Fas, FasL, TNF, caspase-3, -8, and -9, Bid, and Bax. In accordance with these findings, cigarette smoke induced pulmonary inflammation, DNA injury, apoptosis, and emphysema via an IFN-gamma-dependent pathway(s), and a null mutation of CCR5 decreased these responses. These studies demonstrate that IFN-gamma is a potent stimulator of CC and CXC chemokines and highlight the importance of CCR5 in the pathogenesis of IFN-gamma-induced and cigarette smoke-induced inflammation, tissue remodeling, and emphysema. They also demonstrate that CCR5 is required for optimal IFN-gamma stimulation of its own ligands, other chemokines, MMPs, caspases, and cell death regulators and the inhibition of antiproteases.
authors.affiliation: Section of Pulmonary and Critical Care Medicine, Yale University School of Medicine, New Haven, Connecticut 06520, USA.
authors.forename: Bing
authors.initials: B
authors.lastname: Ma
authors.forename: Min-Jong
authors.initials: MJ
authors.lastname: Kang
authors.forename: Chun Geun
authors.initials: CG
authors.lastname: Lee
authors.forename: Svetlana
authors.initials: S
authors.lastname: Chapoval
authors.forename: Wei
authors.initials: W
authors.lastname: Liu
authors.forename: Qingsheng
authors.initials: Q
authors.lastname: Chen
authors.forename: Anthony J
authors.initials: AJ
authors.lastname: Coyle
authors.forename: José M
authors.initials: JM
authors.lastname: Lora
authors.forename: Dominic
authors.initials: D
authors.lastname: Picarella
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Homer
authors.forename: Jack A
authors.initials: JA
authors.lastname: Elias
mesh_terms: D000818:Animals; D017304:Annexin A5 / Q000737:chemistry; D017209:Apoptosis; D018893:Bronchoalveolar Lavage; D016923:Cell Death; D018925:Chemokines / Q000378:metabolism; D004247:DNA / Q000378:metabolism; D017931:DNA Primers / Q000737:chemistry; D004646:Emphysema / Q000378:metabolism / Q000473:pathology*; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D007150:Immunohistochemistry; D020287:In Situ Nick-End Labeling; D007249:Inflammation; D007371:Interferon-gamma / Q000378:metabolism*; D008024:Ligands; D008168:Lung / Q000378:metabolism; D008264:Macrophages / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009154:Mutation; D010641:Phenotype; D011650:Pulmonary Alveoli / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D019713:Receptors, CCR5 / Q000378:metabolism / Q000502:physiology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012907:Smoking; D013997:Time Factors
chemical_list: D017304:Annexin A5; D018925:Chemokines; D017931:DNA Primers; D008024:Ligands; D012333:RNA, Messenger; D019713:Receptors, CCR5; D007371:Interferon-gamma; D004247:DNA; D020780:Matrix Metalloproteinase 9