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in the Pathogenesis of IL-13-Induced Inflammation and Remodeling1
,
* Section of Pulmonary and Critical Care Medicine and
Department of Pathology, Yale University School of Medicine, New Haven, CT 06520; and
Pathology and Laboratory Medicine Service, Veterans Affairs-Connecticut Health Care System, West Haven, CT 06516
IL-13 is a major stimulator of inflammation and tissue remodeling at sites of Th2 inflammation. In Th2-dominant inflammatory disorders such as asthma, IL-11 is simultaneously induced. However, the relationship(s) between IL-11 and IL-13 in these responses has not been defined, and the role(s) of IL-11 in the genesis of the tissue effects of IL-13 has not been evaluated. We hypothesized that IL-11, signaling via the IL-11R
-gp130 receptor complex, plays a key role in IL-13-induced tissue responses. To test this hypothesis we compared the expression of IL-11, IL-11R, and gp130 in lungs from wild-type mice and transgenic mice in which IL-13 was overexpressed in a lung-specific fashion. We simultaneously characterized the effects of a null mutation of IL-11R on the tissue effects of transgenic IL-13. These studies demonstrate that IL-13 is a potent stimulator of IL-11 and IL-11R. They also demonstrate that IL-13 is a potent stimulator of inflammation, fibrosis, hyaluronic acid accumulation, myofibroblast accumulation, alveolar remodeling, mucus metaplasia, and respiratory failure and death in mice with wild-type IL-11R loci and that these alterations are ameliorated in the absence of IL-11R. Lastly, they provide insight into the mechanisms of these processes by demonstrating that IL-13 stimulates CC chemokines, matrix metalloproteinases, mucin genes, and gob-5 and stimulates and activates TGF-
1 via IL-11R-dependent pathways. When viewed in combination, these studies demonstrate that IL-11R plays a key role in the pathogenesis of IL-13-induced inflammation and remodeling.
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