IL-13-Induced Chemokine Responses in the Lung: Role of CCR2 in the Pathogenesis of IL-13-Induced Inflammation and Remodeling

Abstract

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)-1α, MIP-1β, MIP-2, MIP-3α, 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 α1-antitrypsin, tissue inhibitor of metalloproteinase-1, -2, and -4, and secretory leukocyte proteinase inhibitor. In addition, the levels of bioactive and total TGF-β1 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.

IL-13 Receptor α2 Selectively Inhibits IL-13-Induced Responses in the Murine Lung

“…1C). As previously reported (30,31), IL-13 significantly increased the levels of mRNA encoding these chemokines in IL-13 Tg mice with WT IL-13R␣2 loci (Fig. 1C).…”

“…Studies in a variety of systems have demonstrated that IL-13 is a major mediator of these fibrotic responses (42,51,56). A number of studies demonstrated that IL-13 causes tissue fibrosis, at least in part, by inducing and activating TGF-␤1 (22,32), which is dependent on MCP-1/CCL2 and MMP-9, respectively (30,32). The present studies add to our understanding of this important fibrogenic pathway by demonstrating that IL-13R␣2 plays a critical role in its regulation.…”

Global Gene Expression Profiles During Acute Pathogen-Induced Pulmonary Inflammation Reveal Divergent Roles for Th1 and Th2 Responses in Tissue Repair

“…Chemokines and their receptors associated with a Th1 response, e.g., RANTES and IFN-inducible protein-10, were increased, attracting neutrophils, monocytes, and lymphocytes (18,19). In contrast, the chemokines expressed by 10/12 KO mice, including MCP-2, MCP-3, and MCP-5, as well as TARC, C10, eotaxin, and eotaxin 2, are increased in mice with enhanced IL-13 expression and mice lacking IFN-␥ (18,20). Likewise, MIP-1␥ has been associated with a Th2 phenotype (18).…”

Versican Deficiency Significantly Reduces Lung Inflammatory Response Induced by Polyinosine-Polycytidylic Acid Stimulation

“…A significant increase in versican accumulation occurs in the interstitial space of small and large airways of patients with asthma (11-13, 15, 46) and in animal models of asthma (17,18). Cells isolated from diseased lungs also exhibit altered versican production.…”