UC manifests as a TH2 cytokine (IL-4, IL-5, and IL-13)-driven erosion of the intestinal epithelium 23, 24, 51–53. On the contrary, Crohn’s colitis is driven by TH1 and TH17 cytokines (IFN-γ, IL-17A/F) 3, 54. Although the etiology of UC remains unclear, recent studies

have focused on the role of IL-33, an IL-1 family cytokine that instructs type 2 inflammation 25. In human UC patients, IL-33 expression is highly upregulated within the intestinal mucosa and IL-33-deficient mice are protected from DSS-induced intestinal immunopathology 23, 24, 55. Our data show that CD68TGF-βDNRII mice produce high levels selleck chemical of IgE and IL-33 within the colon following DSS-induced gut injury. One source of IL-33 in CD68TGF-βDNRII mice was intestinal Mϕs, which demonstrates that TGF-β serves an important role in limiting intestinal inflammation through suppression of IL-33. This may be an important mechanism that could partially explain the reason how mutations in TGF-βRII

in humans are associated with increased risk for UC and UC-associated cancer 19, 20. Thus, it Napabucasin research buy is tempting to speculate that blockade of IL-33 during UC may help to reduce the severity of colitis in these patients. Overall, we demonstrate that mice engineered to have a specific impairment of TGF-β responsiveness in Mϕs develop increased severity of DSS-induced colitis during the resolution phase. This suggests that TGF-β-mediated regulation of Mϕs function serves an important role in the suppression of intestinal inflammation following acute injury. In this regard, it will be important to determine whether CD68TGF-βDNRII mice develop altered susceptibility or resistance to infectious diseases or show defects in tissue repair mechanisms in other model

systems. The Ribonucleotide reductase TGF-βDNRII construct was obtained from Dr. Chung Lee at Northwestern University in a plasmid that encodes the extracellular and transmembrane domains, but lacks the cytoplasmic region for human TGF-β receptor II (−5 to 553), which blocks TGF-β responsiveness in vivo 56. This region was subcloned into a modified pcDNA3.1™ (Invitrogen) using Not 1 and Xho 1. The 1 kb promoter sequence from human CD68 (macrosialin) including the 89 bp intronic enhancer (provided by Peter Murray at St. Jude Hospital) 26 was inserted 5′ to TGF-βDNRII as a BamH1-EcoRV fragment and confirmed by restriction digest and DNA sequencing. CD68TGF-βDNRII mice were generated by pronuclear injection of fertilized C57BL/6 oocytes at the University of Cincinnati Transgenic core facility. Offspring were analyzed for genotype by PCR using primers specific for CD68IVS1 and human TGF-β type II. All mice used in the study were age-matched male mice on a C57BL/6 background. All experiments were performed with age-/sex-matched nontransgenic littermates used as controls.