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J. Biol. Chem., Vol. 282, Issue 46, 33714-33724, November 16, 2007

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Hypoxia-inducible Factor Mediates Hypoxic and Tumor Necrosis Factor -induced Increases in Tumor Necrosis Factor- Converting Enzyme/ADAM17 Expression by Synovial Cells^*

Martine Charbonneau, Kelly Harper, Francine Grondin, Manuela Pelmus, Patrick P. McDonald^¶, and Claire M. Dubois¹

From the Immunology Division, Departments of Pediatrics, Pathology, and ^¶Medicine, Faculty of Medicine, Université de Sherbrooke, Québec J1H 5N4, Canada

Chronic hypoxia and inflammatory cytokines are hallmarks of inflammatory joint diseases like rheumatoid arthritis (RA), suggesting a link between this microenvironment and central pathological events. Because TACE/ADAM17 is the predominant protease catalyzing the release of tumor necrosis factor (TNF), a cytokine that triggers a cascade of events leading to RA, we examined the regulation of this metalloprotease in response to hypoxia and TNF itself. We report that low oxygen concentrations and TNF enhance TACE mRNA levels in synovial cells through direct binding of hypoxia-inducible factor-1 (HIF-1) to the 5' promoter region. This is associated with elevated TACE activity as shown by the increase in TNF shedding rate. By the use of HIF-1-deficient cells and by obliterating NF-B activation, it was determined that the hypoxic TACE response is mediated by HIF-1 signaling, whereas the regulation by TNF also requires NF-B activation. As a support for the in vivo relevance of the HIF-1 axis for TACE regulation, immunohistological analysis of TACE and HIF-1 expression in RA synovium indicates that TACE is up-regulated in both fibroblast- and macrophage-like synovial cells where it localizes with elevated expression of both HIF-1 and TNF. These findings suggest a mechanism by which TACE is increased in RA-affected joints. They also provide novel mechanistic clues on the influence of the hypoxic and inflammatory microenvironment on joint diseases.

Received for publication, May 16, 2007 , and in revised form, August 20, 2007.

^* This work was supported in part by Canadian Institutes for Health Research Grant MOP-68944 (to C. M. D.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Figs. S1 and S2.

¹ Member of the FRSQ-funded Centre de Recherche de Recherche Clinique Étienne Lebel. To whom correspondence should be addressed. Tel.: 819-564-5289; Fax: 819-564-5215; E-mail: Claire.M.Dubois{at}usherbrooke.ca.

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