, 2005; Mills and Dunne, 2009). In brief, the protective function of these mediators, which involves epithelial cell repair, contrasts http://www.selleckchem.com/products/crenolanib-cp-868596.html with their pathogenic role in maintaining intestinal inflammation. The increased production of IL-1�� by HLA-DR+CD172a+ cells at inflamed sites in CD patients reinforces the idea that the overproduction of IL-1�� correlates with overt inflammation and enhanced disease susceptibility in CD patients with Nod2 mutations (Villani et al., 2009). Here, we further demonstrated that CD47 fusion protein profoundly alters the in vitro proinflammatory cytokine profile released from inflamed mucosal explants, including those extracted from patients who were refractory to anti-TNF therapy. More specifically, exposure to CD47-Var1 disabled HLA-DR+CD172a+ cells by reducing IL-1��, IL-6, IL-8, TNF, and, to a lesser extent, IL-23 release.

CD47-Var1 also reduced IL-10 production. Although intestinal epithelial cells represent a major source of IL-10 in noninflamed gut tissues, the release of IL-10 was augmented in inflamed colons, corroborating earlier studies (Autschbach et al., 1998). These data suggest that local IL-10 is insufficient to control overt inflammation in CD colons. In that regard, treatment with IL-10 does not ameliorate human CD nor established murine experimental colitis (Herfarth and Sch?lmerich, 2002). Furthermore, TNF, IL-6, and IL-8 secretion was restricted to CD172a+ cells, that include HLA-DR+ (inflammatory DCs) and HLA-DR? cells (neutrophils) in the LP of CD patients. The frequency of IL-23+CD68+ M�� is augmented in situ in inflamed tissues (Schenk et al.

, 2007). Together with IL-23, IL-1�� can promote the generation of Th17 cells (Acosta-Rodriguez et al., 2007). Recent studies have supported the concept that CD is a Th1/Th17-associated autoinflammatory disease (Kobayashi et al., 2008). Our data indicate that CD47-Var1 impaired the ability of HLA-DR+CD172a+ CX3CR1? cells isolated from mLNs of CD donors, to stimulate in vitro memory Th17, Th17/Th1 but not Th1 responses. The CD47 fusion protein, when administered in vivo, could also reduce the recruitment of colitogenic CD172a+ cells to tissues and mLNs (Fortin et al., 2009). In that regard, our results indicate that CD47-Var1 decreased the production of MIP-1��, which is Brefeldin_A reported to attract inflammatory monocytes to inflamed gut (Schulthess et al., 2012). Collectively, we have identified functional HLA-DR+CD172a+ cells, which are increased in the mLNs and intestines of CD patients, and conclude that these cells represent the human counterparts of murine colitogenic DCs. Confusion still remains regarding the classification of these mononuclear phagocytes as Mo-DCs or M�� in peripheral tissues.