IL-11 Receptor α in the Pathogenesis of IL-13-Induced Inflammation and Remodeling

Chen, Qingsheng; Rabach, Lesley A.; Noble, Paul W.; Zheng, Tao; Lee, Chang-Min; Homer, Robert J.; Elias, Jack A.

doi:10.4049/jimmunol.174.4.2305

Cited by 68 publications

(51 citation statements)

References 63 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…A variety of lines of evidence suggests that the consequences of hyperoxia are mediated and regulated, at least in part, by the ability of 100% O 2 to induce a variety of cytokine-receptor pathways (14,(25)(26)(27)(28)(29)(30)(31). In the majority of these studies, the cytokine ligand is induced and is presumed to mediate its effects by binding to its unaltered receptor (14,(25)(26)(27)(28)(29)31).…”

Section: Discussionmentioning

confidence: 99%

Increased Hyperoxia-Induced Mortality and Acute Lung Injury in IL-13 Null Mice

Bhandari

Choo-Wing

Homer

et al. 2007

The Journal of Immunology

Self Cite

View full text Add to dashboard Cite

IL-13 is a critical effector at sites of Th2 inflammation and remodeling. As a result, anti-IL-13-based therapies are being actively developed to treat a variety of diseases and disorders. However, the beneficial effects of endogenous IL-13 in the normal and diseased lung have not been adequately defined. We hypothesized that endogenous IL-13 is an important regulator of oxidant-induced lung injury and inflammation. To test this hypothesis, we compared the effects of 100% O2 in mice with wild-type and null IL-13 loci. In this study, we demonstrate that hyperoxia significantly augments the expression of the components of the IL-13R, IL-13Rα1, and IL-4Rα. We also demonstrate that, in the absence of IL-13, hyperoxia-induced tissue inflammation is decreased. In contrast, in the IL-13 null mice, DNA injury, cell death, caspase expression, and activation and mortality are augmented. Interestingly, the levels of the cytoprotective cytokines vascular endothelial cell growth factor, IL-6, and IL-11 were decreased in the bronchoalveolar lavage fluid. These studies demonstrate that the expression of the IL-13R is augmented and that the endogenous IL-13-IL-13R pathway contributes to the induction of inflammation and the inhibition of injury in hyperoxic acute lung injury.

show abstract

Section: Discussionmentioning

confidence: 99%

Increased Hyperoxia-Induced Mortality and Acute Lung Injury in IL-13 Null Mice

Bhandari

Choo-Wing

Homer

et al. 2007

The Journal of Immunology

Self Cite

View full text Add to dashboard Cite

show abstract

“…One of the fundamental research questions in deciphering the interplay of infection and asthma is: which innate pathways are deficient in asthmatic airways so an infection could prevail? Although the effects of allergic inflammation or Th2 cytokines on airway hyperreactivity and remodeling (e.g., fibrosis and mucus production) have been relatively well investigated (31)(32)(33), little is known about the role of a Th2 cytokine milieu in regulating the airway epithelial innate immune response to infections. Early observations suggested that SPLUNC1 protein decreased in the nasal lavage fluid of human subjects exposed to allergens and irritants such as cigarette smoke (34 -38).…”

Section: Discussionmentioning

confidence: 99%

Function and Regulation of SPLUNC1 Protein in Mycoplasma Infection and Allergic Inflammation

Chu¹,

Thaikoottathil²,

Rino³

et al. 2007

The Journal of Immunology

119

150

View full text Add to dashboard Cite

Respiratory infections, including Mycoplasma pneumoniae (Mp), contribute to asthma pathobiology. To date, the mechanisms underlying the increased susceptibility of asthmatics to airway Mp infection remain unclear. Short palate, lung, and nasal epithelium clone 1 (SPLUNC1) protein is a recently described large airway epithelial cell-derived molecule that was predicted to exert host defense activities. However, SPLUNC1 function and regulation in an infectious or allergic milieu are still unknown. We determined host defense and anti-inflammatory functions of SPLUNC1 protein in Mp infection and the regulation of SPLUNC1 by Mp and allergic inflammation (e.g., IL-13). SPLUNC1 function was examined in Mp or human airway epithelial cell cultures by using SPLUNC1 recombinant protein, overexpression and RNA interference. Human and mouse bronchial epithelial SPLUNC1 was examined using immunostaining, Western blotting, ELISA, laser capture microdissection, and real-time PCR. Mouse models of Mp infection and allergic inflammation and air-liquid interface cultures of normal human primary bronchial epithelial cells were used to study SPLUNC1 regulation by Mp and IL-13. We found that: 1) SPLUNC1 protein decreased Mp levels and inhibited epithelial IL-8 production induced by Mp-derived lipoproteins; 2) normal human and mouse large airway epithelial cells expressed high levels of SPLUNC1; and 3) although Mp infection increased SPLUNC1, IL-13 significantly decreased SPLUNC1 expression and Mp clearance. Our results suggest that SPLUNC1 serves as a novel host defense protein against Mp and that an allergic setting markedly reduces SPLUNC1 expression, which may in part contribute to the persistent nature of bacterial infections in allergic airways.

show abstract

“…To test this hypothesis, we compared the expression of IL-11, IL-11R␣, and gp130 in lungs from wild-type mice and IL-13 OE transgenic mice. We simultaneously characterized the effects of a null mutation of IL-11R␣ on the tissue effects of transgenic IL-13 (43). These studies demonstrate that IL-13 is a potent stimulator of IL-11 and IL-11R␣.…”

Section: Mechanisms Of Airway Fibrosismentioning

confidence: 99%

Transgenic Modeling of Transforming Growth Factor- 1: Role of Apoptosis in Fibrosis and Alveolar Remodeling

Lee

Kang²,

Homer³

et al. 2006

Proceedings of the American Thoracic Society

105

View full text Add to dashboard Cite

Inflammation and tissue remodeling with pathologic fibrosis are common consequences of Th2 responses in the lung and other organs. Interleukin (IL)-13 and transforming growth factor-␤1 (TGF-␤ 1 ) are frequently coexpressed in these responses and are believed to play important roles in the pathogenesis of Th2-induced pathologies. To shed light on the mechanisms of these responses, overexpression transgenic approaches were used to selectively target each of these cytokines to the murine lung. IL-13 proved to be a potent stimulator of eosinophilic inflammation, mucus metaplasia, tissue fibrosis, and alveolar remodeling. CC chemokines, specific chemokine receptors (CCR2, CCR1), adenosine metabolism, vascular endothelial growth factor, and IL-11 contributed to the genesis of these responses. IL-13 also induced tissue fibrosis, at least in part, via its ability to induce and activate TGF-␤ 1 . In the TGF-␤ 1 transgenic mouse, epithelial apoptosis preceded the onset of tissue fibrosis and alveolar remodeling. In addition, chemical (Z-VAD-fmk) and genetic (null mutations of early growth response gene 1) interventions blocked apoptosis and ameliorated TGF-␤ 1 -induced fibrosis and alveolar restructuring. These studies define an IL-13-TGF-␤ 1 pathway of tissue remodeling that regulates inflammation, mucus metaplasia, apoptosis, vascular responses, and fibrosis in the lung. They also highlight the intimate relationship between apoptosis and fibrosis induced by TGF-␤ 1 . By defining the complexities of this pathway, these studies highlight sites at which therapies can be directed to control these important responses.

show abstract

IL-11 Receptor α in the Pathogenesis of IL-13-Induced Inflammation and Remodeling

Cited by 68 publications

References 63 publications

Increased Hyperoxia-Induced Mortality and Acute Lung Injury in IL-13 Null Mice

Increased Hyperoxia-Induced Mortality and Acute Lung Injury in IL-13 Null Mice

Function and Regulation of SPLUNC1 Protein in Mycoplasma Infection and Allergic Inflammation

Transgenic Modeling of Transforming Growth Factor- 1: Role of Apoptosis in Fibrosis and Alveolar Remodeling

Contact Info

Product

Resources

About