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Role of CC Chemokine Receptor 5 in Interferon-– and Cigarette Smoke–induced Emphysema

Section of Pulmonary and Critical Care Medicine, and Department of Pathology, Yale University, New Haven, Connecticut; and Millennium Pharmaceutical, Inc., Boston, Massachusetts

Correspondence and requests for reprints should be addressed to Jack A. Elias, M.D., Yale University School of Medicine, Pulmonary & Critical Care Medicine, 300 Cedar Street, S441 TAC, New Haven, CT 06520–8057. E-mail: jack.elias{at}yale.edu

Th1 inflammation and remodeling responses characterized by tissue atrophy and destruction frequently coexist in human diseases. To further understand the mechanisms of these responses, studies were undertaken to define the role(s) of CC chemokine receptor 5 (CCR5) in the pathogenesis of IFN-–induced inflammation and remodeling in a murine model of pulmonary emphysema. IFN- was a potent stimulator of the CCR5 ligands, MIP-1/CCL-3, MIP-1ß/CCL-4, and RANTES (regulated upon activation, T-cell expressed and secreted)/CCL-5. IFN- also stimulated MCP-1/CCL-2, MCP-2/CCL-8, MCP-5/CCL-12, MIP-2/CXCL2/3, KC/CXCL-1, ENA 78/CXCL-5, Mig/CXCL-9, IP-10/CXCL-10, I-TAC/CXCL-11, SDF-1/CXCL-12, C10/CCL-6, MDC/CCL-22, and TECK/CCL25. Antibody neutralization or null mutation of CCR5 decreased IFN-–induced inflammation, DNA injury, and apoptosis and alveolar remodeling. These interventions decreased the expression of select chemokines (MIP-1/CCL-3, MIP-1ß/CCL-4, MIP-2/CXCL-2/3, RANTES/CCL-5, MCP-1/CCL-2, KC/CXCL-1, and IP-10/CXCL-10) and matrix metalloproteinase (MMP)-9 and increased the expression of SLPI. The alterations in DNA injury and apoptosis were associated with decreased expression of Fas, Fas-L, tumor necrosis factor (TNF), caspases 3, 8, and 9, Bid, and Bax, and decreased activation of Bid and caspases 3, 8, and 9. In accord with these findings, a null mutation of CCR5 also decreased the inflammation, DNA injury, cell death, and emphysema caused by cigarette smoke exposure. These studies demonstrate that IFN- is a potent stimulator of a variety of CC and CXC chemokines and highlight the importance of CCR5 in the pathogenesis of IFN-– and cigarette smoke–induced inflammation, tissue remodeling, and emphysema. They also demonstrate that CCR5 is required for optimal IFN- stimulation of its own ligands and other chemokines, MMPs, caspases, and extrinsic and intrinsic cell death regulators and the inhibition of SLPI.

FOOTNOTES

Conflict of Interest Statement: None of the authors has a financial relationship with a commercial entity that has an interest in the subject of this manuscript.

(Received in original form March 20, 2006; accepted in final form March 28, 2006)

This Article Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Ma, B. Articles by Elias, J. A. Search for Related Content PubMed Articles by Ma, B. Articles by Elias, J. A.