The infected mice displayed a significant up-regulation in the expression of chemokines (Cxcl1, Cxcl2 and Ccl2), numerous pro-inflammatory cytokines (Ifng, Il1b, Il6, and Il17f), as well as Il22 and a number of anti-microbial peptides (Defa1, Defa28, Defb1, Slpi and Reg3g) at the site(s) of infection. This was accompanied by a significant influx of neutrophils, BAY 57-1293 dendritic cells, cells of the monocyte/macrophage lineage and all major subsets of lymphocytes to these site(s). However, CD4 T cells of the untreated and C. difficile-infected mice expressed similar levels of CD69 and CD25. Neither tissue had up-regulated levels of Tbx21, Gata3 or Rorc. The caeca and colons of the

infected mice showed a significant increase in eukaryotic initiation factor 2α (eIF2α) phosphorylation, but neither the splicing of Xbp1 nor the up-regulation of endoplasmic reticulum chaperones, casting doubt on the full-fledged induction of the unfolded protein response by C. difficile. They also displayed significantly higher phosphorylation of AKT and signal transducer and activator of transcription 3 (STAT3), an indication of pro-survival signalling. These data

underscore the local, innate, pro-inflammatory nature of the response to C. difficile and highlight eIF2α phosphorylation and the interleukin-22–pSTAT3–RegIIIγ axis as two of the pathways that could be used to contain and counteract the damage inflicted on the intestinal Pictilisib in vitro epithelium. Clostridium difficile is a Gram-positive, spore-forming, anaerobic bacterium.[1] It is the most prevalent cause of infectious Non-specific serine/threonine protein kinase diarrhoea in antibiotic-treated patients in hospitals.[2, 3] Infection with C. difficile can lead to a broad range of clinical outcomes, including asymptomatic colonization, mild diarrhoea and severe pseudomembranous colitis. Clostridium difficile encodes a number of toxins. Of these, two exotoxins, TcdA and TcdB, are the bacterium’s main virulence factors. Both toxins are glucosyltransferases that irreversibly inactivate small GTPases of the Rho family.[4, 5] This in turn leads to the depolymerization of the epithelial actin cytoskeleton, impaired function of tight junctions and severe epithelial cell damage.[6-8] The use of

ileal loop models has provided useful insights into the function of these toxins.[9] Studies using mouse models of C. difficile infection have proven the higher susceptibility of MyD88−/−[10] and Toll-like receptor 4−/−[11] mice and the protective effect of Toll-like receptor 5 stimulation against acute C. difficile colitis.[12] The higher susceptibility of MyD88−/− mice is at least in part due to impaired CXCL1 expression and the consequent reduction in neutrophil influx to the site of infection.[13] Interestingly, NOD1−/− mice also have reduced neutrophil recruitment to the site of infection, but show similar levels of epithelial damage as wild-type mice.[14] However, much remains to be determined about the host inflammatory and mucosal response to C.