The Metalloprotease-Disintegrin ADAM8 Is Essential for the Development of Experimental Asthma

Naus, Silvia; Blanchet, Marie Renée; Gossens, Klaus; Zaph, Colby; Bartsch, Jörg W.; McNagny, Kelly M.; Ziltener, Hermann J.

doi:10.1164/rccm.200909-1396oc

Cited by 61 publications

(64 citation statements)

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“…For instance, Mmp8 2/2 mice display higher neutrophilic inflammation, being the consequence of a lack of LIX processing that delays apoptosis of these cells (12,(43)(44)(45). Adam8 2/2 mice display less eosinophilic inflammation (22) and impaired dendritic cell recruitment (15,22). Adamts12 deletion leads to hyperresponsiveness associated with enhanced eosinophil and mast cell infiltration.…”

Section: Discussionmentioning

confidence: 99%

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Control of Allergen-Induced Inflammation and Hyperresponsiveness by the Metalloproteinase ADAMTS-12

Paulissen

Hour

Rocks

et al. 2012

The Journal of Immunology

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A disintegrin and metalloproteinase with thrombospondin motifs (ADAMTS) constitute a family of endopeptidases related to matrix metalloproteinases. These proteinases have been largely implicated in tissue remodeling associated with pathological processes. Among them, ADAMTS12 was identified as an asthma-associated gene in a human genome screening program. However, its functional implication in asthma is not yet documented. The present study aims at investigating potential ADAMTS-12 functions in experimental models of allergic airways disease. Two different in vivo protocols of allergen-induced airways disease were applied to the recently generated Adamts12-deficient mice and corresponding wild-type mice. In this study, we provide evidence for a protective effect of ADAMTS-12 against bronchial inflammation and hyperresponsiveness. In the absence of Adamts12, challenge with different allergens (OVA and house dust mite) led to exacerbated eosinophilic inflammation in the bronchoalveolar lavage fluid and in lung tissue, along with airway dysfunction assessed by increased airway responsiveness following methacholine exposure. Furthermore, mast cell counts and ST2 receptor and IL-33 levels were higher in the lungs of allergen-challenged Adamts12-deficient mice. The present study provides, to our knowledge, the first experimental evidence for a contribution of ADAMTS-12 as a key mediator in airways disease, interfering with immunological processes leading to inflammation and airway hyperresponsiveness.

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Section: Discussionmentioning

confidence: 99%

“…These membraneassociated enzymes bear multifunctional domains, including a catalytic domain, a disintegrin domain, and a cysteine-rich domain (18). Their expression is increased in asthmatic patients (19,20) and in murine asthma models (21,22). ADAM33 is the first asthma susceptibility gene that has been recognized by positional cloning (16).…”

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confidence: 99%

Control of Allergen-Induced Inflammation and Hyperresponsiveness by the Metalloproteinase ADAMTS-12

Paulissen

Hour

Rocks

et al. 2012

The Journal of Immunology

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“…In addition, we demonstrated that ORMDL3 selectively regulates activation of the ER localized transcription factor ATF6α signaling branch, a pathway we have demonstrated in human lung epithelial cells is linked to SERCA-2b, which is implicated in airway remodeling in asthma (24). Finally, our studies demonstrate that ORMDL3 activates several metalloprotease, chemokine, and OAS-regulated genes, several of whom have also been implicated in the pathogenesis of asthma (7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19)(20)(21)(22)(23)(24). Overall, these studies provide evidence for a mechanism to link an ER localized protein such as ORMDL3 to the pathogenesis of asthma.…”

Section: Discussionmentioning

confidence: 72%

“…The importance of these ORMDL3-regulated genes to asthma is suggested from studies demonstrating increased expression of many of these mediators in the airways of human asthmatics (MMP-9, ADAM-8, CCL-20, CXCL-10, IL-8) (7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17), induction of these mediators by allergen inhalation in asthmatics (MMP-9, CCL-20, CXCL-10) (7,12,19), and inhibition of asthma outcomes in mice deficient in these genes (MMP-9, ADAM-8, CXCL-10) (8,9,11,20,21). In addition to the important role of CCL-20 on T-cell recruitment (12), and epithelial mucus production (14), in mouse models of asthma, there is a critical link between CCL-20 and TRAIL for Th2 cell activation and allergic airway inflammation (15).…”

Section: Discussionmentioning

confidence: 99%

ORMDL3 is an inducible lung epithelial gene regulating metalloproteases, chemokines, OAS, and ATF6

Miller

Tam²,

Cho³

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

173

264

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Orosomucoid like 3 (ORMDL3) has been strongly linked with asthma in genetic association studies, but its function in asthma is unknown. We demonstrate that in mice ORMDL3 is an allergen and cytokine (IL-4 or IL-13) inducible endoplasmic reticulum (ER) gene expressed predominantly in airway epithelial cells. Allergen challenge induces a 127-fold increase in ORMDL3 mRNA in bronchial epithelium in WT mice, with lesser 15-fold increases in ORMDL-2 and no changes in ORMDL-1. Studies of STAT-6–deficient mice demonstrated that ORMDL3 mRNA induction highly depends on STAT-6. Transfection of ORMDL3 in human bronchial epithelial cells in vitro induced expression of metalloproteases (MMP-9, ADAM-8), CC chemokines (CCL-20), CXC chemokines (IL-8, CXCL-10, CXCL-11), oligoadenylate synthetases (OAS) genes, and selectively activated activating transcription factor 6 (ATF6), an unfolded protein response (UPR) pathway transcription factor. siRNA knockdown of ATF-6α in lung epithelial cells inhibited expression of SERCA2b, which has been implicated in airway remodeling in asthma. In addition, transfection of ORMDL3 in lung epithelial cells activated ATF6α and induced SERCA2b. These studies provide evidence of the inducible nature of ORMDL3 ER expression in particular in bronchial epithelial cells and suggest an ER UPR pathway through which ORMDL3 may be linked to asthma.

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“…Members of the ADAM family function as sheddases by cleaving type I and type II integral single membrane proteins to generate soluble forms of these proteins (5) and have been found to be involved in the etiologies of a variety of diseases and conditions (6)(7)(8). Members of the ADAM family can degrade the extracellular matrix (ECM) and control cell adhesion and movement through regulation of intercellular adhesion, protease activity and cell activities that are closely related to the metastasis of human tumors (9,10).…”

Section: Introductionmentioning

confidence: 99%

ADAM10 is overexpressed in human hepatocellular carcinoma and contributes to the proliferation, invasion and migration of HepG2 cells

Shao

Shi

2013

Oncology Reports

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Abstract.The overexpression of A disintegrin and metalloproteinase 10 (ADAM10) has been found to be closely associated with the development and progression of various types of tumors. However, ADAM10 expression in hepatocellular carcinoma (HCC) and its significance remain largely unknown. The present study aimed to investigate the expression of ADAM10 in human HCC and the effect of ADAM10 gene silencing by siRNA on the proliferation, invasion and migration of HepG2 human hepatoma cells. Immunohistochemistry was performed to examine the expression of ADAM10 in human HCC tissues and in the adjacent non-cancer tissues from 30 patients with HCC. RNA interference was used to knock down ADAM10 expression in HepG2 human hepatoma cells and the proliferation and migration as well as the invasive ability of the treated cells were observed in vitro. The expression of ADAM10 protein in HCC tissues was significantly higher when compared to that in adjacent non-tumor tissues (P<0.05). The high expression of ADAM10 in cancer was significantly correlated with clinical outcomes (P<0.05). Silencing of ADAM10 resulted in inhibition of proliferation and migration as well as invasion of HepG2 human hepatoma cells (P<0.05). These studies suggest that ADAM10 plays an important role in regulating proliferation, invasion and migration of HepG2 cells. High expression of ADAM10 may be a valuable predictive factor for HCC prognosis, and ADAM10 is potentially an important therapeutic target for the prevention of tumor development and progression in HCC.

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The Metalloprotease-Disintegrin ADAM8 Is Essential for the Development of Experimental Asthma

Cited by 61 publications

References 50 publications

Control of Allergen-Induced Inflammation and Hyperresponsiveness by the Metalloproteinase ADAMTS-12

Control of Allergen-Induced Inflammation and Hyperresponsiveness by the Metalloproteinase ADAMTS-12

ORMDL3 is an inducible lung epithelial gene regulating metalloproteases, chemokines, OAS, and ATF6

ADAM10 is overexpressed in human hepatocellular carcinoma and contributes to the proliferation, invasion and migration of HepG2 cells

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