By using BM chimeras, TSLPR on non-hematopoietic cells was sufficient for SLPI expression and survival

By using BM chimeras, TSLPR on non-hematopoietic cells was sufficient for SLPI expression and survival. conditioning of dendritic cells (DCs) to drive Th2 skewing of T cells (Ito et al., 2005), enhanced class switching in B cells (Xu et al., 2007), and induction of Foxp3+regulatory T (Treg) cells in humans (Watanabe et al., 2005) but not mice (Sun et al., GKT137831 2007). TSLP expression is usually increased in immunopathologies with dysregulated Th2 cell-type cytokine production including atopic dermatitis (Soumelis et al., 2002), and asthma (Ying et al., 2005). While the pathophysiological features of these diseases can be recapitulated in mice over-expressing TSLP (Headley et al., 2009), decreased production of TSLP has been observed in mucosal biopsies from patients with inflammatory bowel disease (IBD) (Rimoldi et al., 2005). Regulation of TSLP is dependent around the transcription factor NF-B, and is induced by exposure to bacteria (Rimoldi et al., 2005), agonists of toll-like receptor (TLR) or the intracellular sensor NOD, (Lee and Ziegler, 2007;Zaph et al., 2007) and cytokines including TNF (Lee et al., 2008). In the beginning suggested as a mechanism to allow the commensal microbiota to induce tolerance, TSLP produced by intestinal epithelial cells is not required for tolerogenic mucosal DC, and Treg cell generation GKT137831 (Iliev et al., 2009). Even though etiology of IBD has remained elusive, immuno-pathology results from loss of immunosuppressive or enhanced production of pro-inflammatory factors. Self-resolving immuno-pathology that recapitulates the hallmarks of colitis in patients can be induced in mice by addition of dextran sodium sulfate (DSS) to drinking water. Inflammation in this model is due to epithelial cell apoptosis, increasing recruitment and activation of macrophages (Tlaskalova-Hogenova et al., 2005), DCs (Berndt et al., 2007), and neutrophils (Okayasu et al., 1990). While T-cell activation and mucosal homing occur, T-cells are not necessary for disease (Katakura et al., 2005). The producing inflammation is usually associated with structural changes in the colon due to increased activity of proteases including neutrophil elastase (NE) and metallomatrix proteases (MMPs) (Castaneda et al., 2005). Recovery following inflammation is usually a complex process requiring not only suppression of immune processes, but also balance between proteolytic enzymes and their endogenous inhibitors. Secretory leukocyte peptidase inhibitor (SLPI) is usually induced by microbial products, functioning as a serine protease inhibitor, anti-microbial peptide, and inhibitor of NF-B (Taggart et al., 2005). SLPI is usually increased during resolution from DSS colitis (Mizoguchi et al., 2003), and exerts a non-redundant role following injury, as SLPI deficiency reduces cutaneous wound healing (Ashcroft et al., 2000). TSLP in the gastrointestinal tract has been explained to inhibit Th1 cell type cytokine production following insult. Although in a previous publication increased IFN production was observed in mice deficient for the TSLP receptor (Crlf2-/-), potentiating the severity of DSS colitis (Taylor et al., 2009); here we statement that deficiency in TSLP ligand did not increase colitis severity, but prevented recovery from disease. Recovery from colitis occurred through signaling transduced by TSLPR on radio-resistant host cells, as mortality was not increased inCrlf2+/+mice INF2 antibody reconstituted GKT137831 withCrlf2-/-bone marrow (BM). Our data demonstrates that TSLP functions as a critical mediator controlling the GKT137831 balance between host defense and wound repair, without constraining production of Th1 cytokines. == Results == == Deficiency in TSLP does not alter immune cell development == The requirement for TSLP in the development and maintenance of B- and T-cell populations was assayed in TSLP wild-type (Tslp+/+), and deficient (Tslp-/-) mice. Consistent with a lack of a requirement for TSLP in murine.