To more accurately assess the uPA-associated alterations in the i

To more accurately assess the uPA-associated alterations in the inflammatory response after DSS-induced colonic mucosa injury, we examined the colon AZD8055 nmr of mice at an early time point after DSS treatments, i.e., 1 week

after the last DSS cycle. We found that DSS-treated mice presented foci of colonic dysplastic glands, which in the long term have been reported to evolve to neoplasia through a well-characterized sequence of events [33], [45] and [46]. We hypothesized that preneoplastic lesions in the colon of uPA−/− + DSS mice may have thrived and evolved into well-sized polyps due to a particular tumor-promoting inflammatory milieu. At 1 week after DSS treatment, we found that uPA−/− + DSS and WT + DSS mice had numerous dysplastic lesions in comparable numbers. However, uPA deficiency Epacadostat order significantly correlated with a more advanced grade of the dysplastic lesions. This finding co-existed with a more robust infiltration of neutrophils and macrophages and an inflammatory response characterized by significantly elevated levels of pro-inflammatory cytokines, such as TNF-α, IL-17, and especially IL-6. The concomitant elevation of the anti-inflammatory cytokine IL-10 was evidently unable

to downregulate these inflammatory cells and cytokines, which have been shown to promote carcinogenesis in the colon and other sites PAK5 [6], [7], [9], [53] and [64]. The uPA−/− + DSS mouse colitis was also different from the one in WT + DSS mice in that it exhibited less T-lymphocytes in the ulcerative lesions and the remaining colonic lamina propria and more in the organized lymphoid tissue of the bowel. Likewise, the Foxp3 + suppressive

subset of T-lymphocytes (Treg) followed a similar pattern. This finding suggests that T-lymphocytes and Treg accumulate in the organized lymphoid bowel tissue and MLN of uPA−/− + DSS mice, but their translocation in the damaged mucosa is retarded. This is probably due to their reduced mobility because of the altered cell–extracellular matrix interactions caused by the lack of uPA-mediated proteolysis [11] and [61]. Our findings regarding Treg are interesting, given the debated role of this immune-suppressive subset of lymphocytes in carcinogenesis [53], [65] and [66]. Indeed, the roles of Treg in cancer appear paradoxical. Studies correlating high densities of tumor-associated Treg with poor prognosis in several types of human cancers are now challenged by studies on the same types of cancer demonstrating correlation with longer survival of patients [67], [68], [69], [70], [71] and [72].

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