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,
*
Section of Pulmonary and Critical Care Medicine, Departments of Internal Medicine and
Pathology, Yale University School of Medicine, New Haven, CT 06520;
Pathology and Laboratory Medicine Service, Veterans Affairs-Connecticut Health Care System, West Haven, CT 06516; and
San Francisco General Hospital, Gladstone Institution of Cardiovascular Division, University of California, San Francisco, CA 94143
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)-1
, MIP-1
, MIP-2,
MIP-3, 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 1-antitrypsin, tissue inhibitor of
metalloproteinase-1, -2, and -4, and secretory leukocyte proteinase
inhibitor. In addition, the levels of bioactive and total
TGF-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.
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