Data are pooled from at least three indie experiments. 1997;Mennechet et al., 2002). Activation of CD4+T cells by IL-12 and IL-18 is critical for AZD4547 the development of small intestinal pathology (Vossenkmper et al., 2004). Recently, we showed that LPS derived from gut flora via Toll-like receptor (TLR)4 mediatesT. gondiiinduced IGLC1 immunopathology (Heimesaat et al., 2006). Therefore, the immunopathogenesis ofT. gondiiinduced small intestinal pathology resembles key features of the inflammatory reactions AZD4547 in inflammatory bowel disease (IBD) in AZD4547 humans and in models of experimental colitis in rodents (Liesenfeld, 2002). However, most animal models of IBD assessed inflammatory reactions in the large intestine, and models of small intestinal pathology are scarce (Kosiewicz et al., 2001;Strober et al., 2002;Olson et al., 2004;Heimesaat et al., 2006). IL-12 shares the p40 subunit, IL-12R1, and components of the signaling transduction pathways with IL-23 (Parham et al., 2002). There is strong evidence that IL-23, rather than IL-12, is important in the development of colitis (Yen et al., 2006). The association of IL-23R encoding variant Arg381Gln with IBD (Duerr et al., 2006) and the up-regulation of IL-23p19 in colon biopsies from individuals with Crohn’s disease (Schmidt et al., 2005) underline the importance of IL-23 in intestinal swelling. Effector mechanisms of IL-23 include the up-regulation of matrixmetalloproteinases (MMPs;Langowski et al., 2006), a large family of endopeptidases that mediate homeostasis of the extracellular matrix. MMPs were significantly up-regulated in experimental models of colitis (Tarlton et al., 2000;Medina et al., 2003) and in colonic cells of IBD individuals (von Lampe et al., 2000). Studies in mouse models of autoimmune diseases have connected the pathogenic part of IL-23 with the build up of CD4+T cells secreting IL-17, termed Th17 cells (Aggarwal et al., 2003;Cua et al., 2003). Moreover, increased IL-17 manifestation was reported in the intestinal mucosa of individuals with IBD (Fujino et al., 2003;Nielsen et al., 2003;Kleinschek et al., 2009). In addition to IL-17, Th17 cells also create IL-22, a member of the IL-10 family (Dumoutier et al., 2000). IL-22, although secreted by particular immune cell populations, does not have any effects on immune cells in vitro or in vivo but regulates functions of some cells cells (Wolk et al., 2009). Interestingly, IL-22 has been proposed to possess both protective as well as pathogenic tasks. In fact, IL-22 mediated psoriasis-like pores and skin alterations (Zheng et al., 2007;Ma et al., 2008;Wolk et al., 2009). In contrast, IL-22 played a protective part in experimental models of colitis (Satoh-Takayama et AZD4547 al., 2008;Sugimoto et al., 2008;Zenewicz et al., 2008;Zheng et al., 2008), inside a model ofKlebsiella pneumoniaeinfection in the lung (Aujla et al., 2007), and against liver damage caused by concanavalin A administration (Radaeva et al., 2004;Zenewicz et al., 2007). IL-22 has been reported to be produced by CD4+T cells (Wolk et al., 2002;Zheng et al., 2007), cells (Zheng et al., 2007), CD11c+cells (Zheng et al., 2008), and natural killer cells (Cella et al., 2008;Luci et al., 2008;Sanos et al., 2009;Satoh-Takayama et al., 2008;Zheng et al., 2008). The part of IL-22 in small intestinal swelling remains to be determined. In the present study, we investigated the role of the IL-23IL-17 axis inT. gondiiinduced small intestinal immunopathology. We display that IL-23 is essential in the development of small intestinal immunopathology by inducing local MMP-2 up-regulation that may be inhibited by prophylactic or restorative chemical blockage. Interestingly, AZD4547 IL-23dependent IL-22 production was markedly up-regulated and essential for the development of ileal swelling, whereas IL-17 production was down-regulated afterT. gondiiinfection. IL-22 was mostly produced by CD4+T cells in the small intestinal lamina propria. == RESULTS == == IL-23 mediatesT. gondiiinduced small intestinal immunopathology == We have previously shown that peroral illness of vulnerable C57BL/6 mice with 100 cysts ofT. gondiiME49 prospects to Th1-type small intestinal necrosis (panileitis;Liesenfeld et al., 1996). To investigate the part of IL-23 in the development of ileal immunopathology, IL-23p19/mice were infected orally. All WT mice died within 10 d after illness, whereas 80% of IL-23p19/mice survived the acute phase of illness (Fig. 1 A). Severe necrosis of the villi and mucosa was observed in.