title: The C10/CCL6 chemokine and CCR1 play critical roles in the pathogenesis of IL-13-induced inflammation and remodeling.
abstract: IL-13 is a potent stimulator of inflammation and tissue remodeling that plays a key role in the pathogenesis of a wide variety of human disorders. To further understand these responses, studies were undertaken to define the role(s) of the chemokine C10/CCL6 in the pathogenesis of IL-13-induced alterations in the murine lung. IL-13 was a very potent stimulator of C10/CCL6 mRNA and protein, and IL-13-induced inflammation, alveolar remodeling, and compliance alterations were markedly ameliorated after C10/CCL6 neutralization. Treatment with anti-C10/CCL6 decreased the levels of mRNA encoding matrix metalloproteinase-2 (MMP-2), MMP-9, and tissue inhibitor of metalloproteinase-4 (TIMP-4) in lungs from wild-type mice. C10/CCL6 neutralization also decreased the ability of IL-13 to stimulate the production of monocyte chemoattractant protein-1, macrophage inflammatory protein-1alpha, MMP-2, MMP-9, and cathepsins-K, -L, and -S and the ability of IL-13 to inhibit alpha1-antitrypsin. In accord with these findings, a targeted null mutation of CCR1, a putative C10/CCL6 receptor, also decreased IL-13-induced inflammation and alveolar remodeling and caused alterations in chemokines, proteases, and antiproteases comparable to those seen after C10/CCL6 neutralization. These C10/CCL6 and CCR1 manipulations did not alter the production of transgenic IL-13. These studies demonstrate that IL-13 is a potent stimulator of C10/CCL6 and highlight the importance of C10/CCL6 and signaling via CCR1 in the pathogenesis of the IL-13-induced pulmonary phenotype. They also describe a C10/CCL6 target gene cascade in which C10/CCL6 induction is required for optimal IL-13 stimulation of selected chemokines (monocyte chemoattractant protein-1 and MIP-1alpha) and proteases (MMP-2, MMP-9, and cathepsins-K, -L, and -S) and the inhibition of alpha1-antitrypsin.
authors.affiliation: Section of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Yale University School of Medicine, New Haven, CT 06520, USA.
authors.forename: Bing
authors.initials: B
authors.lastname: Ma
authors.forename: Zhou
authors.initials: Z
authors.lastname: Zhu
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Homer
authors.forename: Craig
authors.initials: C
authors.lastname: Gerard
authors.forename: Robert
authors.initials: R
authors.lastname: Strieter
authors.forename: Jack A
authors.initials: JA
authors.lastname: Elias
mesh_terms: D000818:Animals; D002403:Cathepsins / Q000096:biosynthesis; D018932:Chemokine CCL2 / Q000096:biosynthesis; D019742:Chemokines, CC / Q000037:antagonists & inhibitors / Q000276:immunology / Q000378:metabolism / Q000502:physiology*; D015536:Down-Regulation / Q000235:genetics / Q000276:immunology; D007106:Immune Sera / Q000008:administration & dosage; D007249:Inflammation / Q000235:genetics / Q000276:immunology* / Q000378:metabolism / Q000503:physiopathology; D018793:Interleukin-13 / Q000008:administration & dosage* / Q000096:biosynthesis / Q000235:genetics; D008168:Lung / Q000276:immunology* / Q000378:metabolism / Q000473:pathology* / Q000503:physiopathology; D008170:Lung Compliance / Q000235:genetics / Q000276:immunology; D008176:Lung Volume Measurements; D020778:Matrix Metalloproteinase 2 / Q000096:biosynthesis; D020780:Matrix Metalloproteinase 9 / Q000096:biosynthesis; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D011480:Protease Inhibitors / Q000378:metabolism; D011650:Pulmonary Alveoli / Q000201:enzymology / Q000276:immunology / Q000473:pathology; D054389:Receptors, CCR1; D019707:Receptors, Chemokine / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D015854:Up-Regulation / Q000235:genetics / Q000276:immunology
chemical_list: C515300:CCR1 protein, human; C515301:Ccr1 protein, mouse; D018932:Chemokine CCL2; D019742:Chemokines, CC; D007106:Immune Sera; D018793:Interleukin-13; D011480:Protease Inhibitors; D054389:Receptors, CCR1; D019707:Receptors, Chemokine; C070959:Ccl6 protein, mouse; D002403:Cathepsins; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9