br Author Contributions br Conflicts

Author Contributions
Conflicts of Interest
Acknowledgments
Introduction ADAMs (a disintegrin and metalloproteinases) are multifunctional proteins involved in ectodomain shedding of transmembrane proteins and thereby regulate cell adhesion, migration, and cell–cell communication. Ectodomain shedding, which is characterized by proteolytic release of extracellular domains of membrane-bound proteins, is a crucial post-translational regulator for the function and availability of membrane-bound proteins. The human U 73343 contains 25 ADAMs including four pseudogenes, and of the 21 ADAM proteins there are 13 proteolytic and 8 nonproteolytic ADAMs (Mochizuki and Okada, 2007, Blobel, 2005, Edwards et al., 2008). Proteolytic ADAMs share the metalloproteinase domain of matrix metalloproteinases (MMPs), and a typical proteolytic ADAM protein is comprised of propeptide, metalloproteinase, disintegrin-like, cysteine-rich, epidermal growth factor (EGF)-like, transmembrane, and cytoplasmic domains (Mochizuki and Okada, 2007, Blobel, 2005, Edwards et al., 2008). Previous studies have shown that several proteolytic ADAM species contribute to inflammatory diseases and cancers by shedding pro-inflammatory cytokines, growth factors and their receptors in addition to the degradation of extracellular proteins including extracellular matrix (ECM) components (Shimoda et al., 2007, 2014, Murphy, 2008). ADAM17, also called tumor necrosis factor (TNF)-α converting enzyme (TACE), was originally identified as a proteinase responsible for the ectodomain shedding of the membrane-bound form of TNF-α (Black et al., 1997). Subsequent studies showed that ADAM17 is also involved in the processing of various membrane-bound molecules including EGF receptor (EGFR) ligands, CD44, Kit ligand and L-selectin (Blobel, 2005). This ectodomain shedding event regulates key functions of these molecules that impact immune responses and cancer development in vivo (Scheller et al., 2011). However, the early lethality of Adam17-deficient mice has hampered the analysis of ADAM17 functions in postnatal development, adult homeostasis and disease (Peschon et al., 1998). To circumvent this issue, we generated conditional Adam17-deficient mice, which exhibit no phenotype in adult animals, enabling us to analyze the roles of ADAM17 in various disease models (Horiuchi et al., 2007, La Marca et al., 2011). Ulcerative colitis (UC) is an intractable inflammatory bowel disease (IBD), showing diffuse mucosal inflammation that extends proximally from the rectum. Onset of UC typically occurs in the second and third decades of life and the majority of affected individuals deteriorate to chronic disease (Farmer et al., 1993, Ordas et al., 2012). Many factors affecting innate and adaptive immunity and epithelial barrier, which include genetic predisposition, eating habits and changes in intestinal flora, may contribute to the complexity of UC, but the underlying mechanisms are still poorly understood (Ananthakrishnan, 2015). Metalloproteinases including ADAMs are produced by many different cell types and regulate intestinal immune responses as well as wound healing (Khokha et al., 2013, Shimoda and Khokha, 2013). Actually, mucosal ADAM17 activity is reported to increase in UC patients (Brynskov et al., 2002). Transient upregulation of ADAM17 activity is implicated in promotion of neutrophil transepithelial migration and high colitis activity (Cesaro et al., 2009) and ADAM17-dependent shedding of TNF-α from intestinal epithelial cells initiates a pro-inflammatory state and mucosal atrophy in a mouse model of total parenteral nutrition (Feng et al., 2015), whereas mice with reduced ADAM17 levels were shown to exhibit increased sensitivity to colitis (Chalaris et al., 2010, Brandl et al., 2010). Therefore, the functions of ADAM17 and the origin of ADAM17-producing cells in UC remain unclear. Previous studies have shown that anti-TNF-α therapy is useful for human inflammatory diseases with excess TNF-α production (Abraham and Cho, 2009), but at present, most of emerging selective ADAM17 inhibitors show various side-effects and are limited to phase I and II trials (Duffy et al., 2011). It is still an open question whether ADAM17 is a promising target for UC treatments.