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.Tumor necrosis factor-␣ converting enzyme (TACE) 2 or ADAM17 was initially described as the predominant enzyme responsible for the physiological cleavage of membrane-anchored tumor necrosis factor-␣ (TNF␣), releasing it in soluble form (1, 2). This enzyme belongs to the ADAM (a disintegrin and metalloprotease domain) family of transmembrane, multidomain zinc metalloproteinases (3) and is expressed in a wide variety of cell types, including TNF␣ non-producing cells (1). Beside TNF␣, TACE was also shown to solubilize a wide variety of proteins including the receptors TNFR-I and TNFR-II (4), interleukin-1RII (5), interleukin-6R (6), and macrophage/colony-stimulating factor-R (7), the cytokine transforming growth factor-␣ (4), members of the membrane-bound epidermal growth factor family (4), the Notch receptor (8), the chemokine fractalkine (9), L-selectin (4), and the -amyloid precursor protein (10). The importance of TACE substrates in a variety of physiological functions, including development, is underscored by the fact that in vivo inhibition of TACE or disruption of the TACE gene results in the death of mice between embryonic day 17.5 and the first day after birth, due to a number of developmental defects. In addition, the implication of TACE substrates in immunoregulation has made this enzyme an efficient therapeutic target in the treatment of a number of pathological conditions including airway inflammation, cancer, and arthritis.Because of the pathophysiological importance of TACE-mediated shedding, several studies have addressed the mechanism of TACE regulation. Sur...