IL-11 receptor alpha in the pathogenesis of IL-13-induced inflammation and remodeling.
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-11Ralpha-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-11Ralpha, 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-11Ralpha on the tissue effects of transgenic IL-13. These studies demonstrate that IL-13 is a potent stimulator of IL-11 and IL-11Ralpha. 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-11Ralpha loci and that these alterations are ameliorated in the absence of IL-11Ralpha. 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-beta1 via IL-11Ralpha-dependent pathways. When viewed in combination, these studies demonstrate that IL-11Ralpha plays a key role in the pathogenesis of IL-13-induced inflammation and remodeling.
Chen
Qingsheng
Q
Section of Pulmonary and Critical Care Medicine, Yale University School of Medicine, New Haven, CT 06520, USA.
Rabach
Lesley
L
Noble
Paul
P
Zheng
Tao
T
Lee
Chun Geun
CG
Homer
Robert J
RJ
Elias
Jack A
JA
D000818:Animals; D019742:Chemokines, CC / Q000096:biosynthesis; D005347:Fibroblasts / Q000473:pathology; D006820:Hyaluronic Acid / Q000378:metabolism; D018496:Hyperoxia / Q000235:genetics / Q000276:immunology; D007249:Inflammation / Q000235:genetics / Q000276:immunology / Q000473:pathology; D017370:Interleukin-11 / Q000378:metabolism*; D053703:Interleukin-11 Receptor alpha Subunit; D018793:Interleukin-13 / Q000096:biosynthesis / Q000235:genetics* / Q000502:physiology; D053661:Interleukin-13 Receptor alpha1 Subunit; D008168:Lung / Q000201:enzymology / Q000276:immunology* / Q000378:metabolism / Q000473:pathology*; D020782:Matrix Metalloproteinases / Q000096:biosynthesis; D008679:Metaplasia; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009077:Mucins / Q000235:genetics; D021122:Protein Subunits / Q000096:biosynthesis / Q000172:deficiency / Q000502:physiology*; D011650:Pulmonary Alveoli / Q000276:immunology / Q000473:pathology; D011658:Pulmonary Fibrosis / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D018123:Receptors, Interleukin / Q000096:biosynthesis / Q000172:deficiency / Q000502:physiology*; D053702:Receptors, Interleukin-11; D053660:Receptors, Interleukin-13; D012131:Respiratory Insufficiency / Q000235:genetics / Q000276:immunology / Q000401:mortality; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology; D016212:Transforming Growth Factor beta / Q000096:biosynthesis / Q000378:metabolism; D053773:Transforming Growth Factor beta1
D019742:Chemokines, CC; C508429:Il11ra1 protein, mouse; C508431:Il11ra2 protein, mouse; C508183:Il13ra1 protein, mouse; D017370:Interleukin-11; D053703:Interleukin-11 Receptor alpha Subunit; D018793:Interleukin-13; D053661:Interleukin-13 Receptor alpha1 Subunit; D009077:Mucins; D021122:Protein Subunits; D018123:Receptors, Interleukin; D053702:Receptors, Interleukin-11; D053660:Receptors, Interleukin-13; C508961:Tgfb1 protein, mouse; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1; D006820:Hyaluronic Acid; D020782:Matrix Metalloproteinases