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Background and Aims In ulcerative colitis [UC], mucosal damage occurs in areas that are infiltrated with neutrophils. The antimicrobial function of neutrophils relies in part on the formation of extracellular web-like structures, named neutrophil extracellular traps [NETs]. The formation and/or clearance of aberrant NETs have been associated with several immune diseases. Here we investigated the role of NETs in UC-related inflammation. Methods The expression of NET-associated proteins was evaluated in colonic biopsies of patients with Crohn's disease [CD], UC and in normal controls [NC] by Western blotting, immunofluorescence and immunohistochemistry. Colonic biopsies of UC patients were analysed before and after anti-tumour necrosis factor α [anti-TNF-α] treatment. The capacity of neutrophils to produce NETs upon activation was tested in vitro. UC lamina propria mononuclear cells [LPMCs] were cultured with NETs in the presence or absence of an extracellular signal-regulated kinase-1/2 [ERK1/2] inhibitor and inflammatory cytokine induction was assessed by real-time polymerase chain reaction and enzyme-linked immunosorbent assay. We also characterized the contribution of NETs in dextran sodium sulfate [DSS]-induced colitis. Results NET-associated proteins were over-expressed in inflamed colon of UC patients as compared to CD patients and NC. Circulating neutrophils of UC patients produced NETs in response to TNF-α stimulation, and reduced expression of NET-related proteins and diminished NET formation were seen in patients receiving successful treatment with anti-TNF-α. Treatment of UC LPMCs with NETs activated ERK1/2, thus enhancing TNF-α and interleukin-1β [IL-1β] production. NETs were induced in mice with DSS-colitis and in vivo inhibition of NET release attenuated colitis. Conclusions Our data show that NET release occurs in UC and suggest a role for NETs in sustaining mucosal inflammation in this disorder. [ABSTRACT FROM AUTHOR]

Background: Colorectal cancer is associated with ulcerative colitis (UC). The infiltration of neutrophils is the main cause of DNA damage produced by inflammation in the intestinal epithelium. Under the action of peptidyl arginine deaminase 4 (PAD4), neutrophils dissociate chromatin and form neutrophil extracellular traps (NETs), which can aggravate tissue inflammation and encourage tumor development. Although Huang Qin Decoction (HQD) was found to be useful in treating UC and was used to gradually prevent and treat digestive tract cancers, the underlying reasons were unclear.Methods: To demonstrate HQD could inhibits the initiation of colitis associated carcinogenesis by controlling NETs related inflammation, we first performed an AOM/DSS-generated colitis-associated carcinogenesis model to assess the efficacy of HQD in reducing neutrophil infiltration and anti-tumor activity. Then, using network pharmacology research, we investigated the potential mechanisms underlying those medicinal effects, as demonstrated by the detection of NETs aggregation and PAD4 expression changes in the colon.Results: HQD substantially reduced the number of colon cancers and the expression of Ki67, restored the level of intestinal tight junction protein occludin and ZO-1, and relieved the intestinal inflammation caused by TNF-α, IL-1β. At the same time, it inhibited neutrophil infiltration in the colon and improved the immunosurveillance of CD8+T cells. The potential mechanisms of HQD intervention against UC and UC with neoplasia (UCN) were studied using network pharmacology, and 156 conjunct genes as well as numerous inflammation-related pathways were identified. Protein-protein interaction (PPI) analysis indicated that HQD inhibition of intestinal tumors might be related to the deactivation of PAD4, which was verified by the down-regulation of NETs, MPO-DNA complex levels, and PAD4 expression after HQD treatment.Conclusion: Huang Qin Decoction inhibits the initiation of colitis associated carcinogenesis by controlling PAD4-dependent neutrophil extracellular traps. [ABSTRACT FROM AUTHOR]