The C10/CCL6 chemokine and CCR1 play critical roles in the pathogenesis of IL-13-induced inflammation and remodeling

J Immunol. 2004 Feb 1;172(3):1872-81. doi: 10.4049/jimmunol.172.3.1872.


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.

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Cathepsins / biosynthesis
  • Chemokine CCL2 / biosynthesis
  • Chemokines, CC / antagonists & inhibitors
  • Chemokines, CC / immunology
  • Chemokines, CC / metabolism
  • Chemokines, CC / physiology*
  • Down-Regulation / genetics
  • Down-Regulation / immunology
  • Immune Sera / administration & dosage
  • Inflammation / genetics
  • Inflammation / immunology*
  • Inflammation / metabolism
  • Inflammation / physiopathology
  • Interleukin-13 / administration & dosage*
  • Interleukin-13 / biosynthesis
  • Interleukin-13 / genetics
  • Lung / immunology*
  • Lung / metabolism
  • Lung / pathology*
  • Lung / physiopathology
  • Lung Compliance / genetics
  • Lung Compliance / immunology
  • Lung Volume Measurements
  • Matrix Metalloproteinase 2 / biosynthesis
  • Matrix Metalloproteinase 9 / biosynthesis
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Mice, Transgenic
  • Protease Inhibitors / metabolism
  • Pulmonary Alveoli / enzymology
  • Pulmonary Alveoli / immunology
  • Pulmonary Alveoli / pathology
  • Receptors, CCR1
  • Receptors, Chemokine / deficiency
  • Receptors, Chemokine / genetics
  • Receptors, Chemokine / physiology*
  • Up-Regulation / genetics
  • Up-Regulation / immunology


  • CCR1 protein, human
  • Ccr1 protein, mouse
  • Chemokine CCL2
  • Chemokines, CC
  • Immune Sera
  • Interleukin-13
  • Protease Inhibitors
  • Receptors, CCR1
  • Receptors, Chemokine
  • Ccl6 protein, mouse
  • Cathepsins
  • Matrix Metalloproteinase 2
  • Matrix Metalloproteinase 9