Cathelicidin-BF, a Novel Antimicrobial Peptide from Bungarus fasciatus, Attenuates Disease in a Dextran Sulfate Sodium Model of Colitis

Abstract

Antimicrobial peptides are molecules of innate immunity. Cathelicidin-BF is the first cathelicidin peptide found in reptiles. However, the immunoregulatory and epithelial barrier protective properties of C-BF have not been reported. Inflammatory bowel diseases, including ulcerative colitis and Crohn's disease, can lead to colon cancer, the third most common malignant tumor. The objective is to develop the new found cathelicidin-BF as a therapeutic to patients of ulcerative colitis. The morphology of the colon epithelium was observed by H&E staining; apoptosis index and infiltration of inflammatory cells in colonic epithelium were measured by TUNEL and immunohistochemistry; the expression level of endogenous mCRAMP was analyzed by immunofluorescence; and phosphorylation of the transcription factors c-jun and NF-κB in colon were analyzed by Western blot. Our results showed that the morphology of the colon epithelium in the C-BF+DSS group was improved compared with the DSS group. Apoptosis and infiltration of inflammatory cells in colonic epithelium were also significantly attenuated in the C-BF+DSS group compared with the DSS group, and the expression level of endogenous mCRAMP in the DSS group was significantly higher than other groups. DSS-induced phosphorylation level of c-jun and NF-κB while C-BF effectively inhibited phosphorylation of NF-κB (p65). The barrier protective effect of C-BF was still excellent. In conclusion, C-BF effectively attenuated inflammation and improved disrupted barrier function. Notably, this is the first report to demonstrate that C-BF attenuates DSS-induced UC both through the regulation of intestinal immune and retention of barrier function, and the exact pathway was through NF-κB.

Cathelicidin-WA Improves Intestinal Epithelial Barrier Function and Enhances Host Defense against Enterohemorrhagic Escherichia coli O157:H7 Infection

“…Differences were determined via a one-way ANOVA followed by a Duncan multiple range test. # p , 0.05 compared with control, *p , 0.05. with this finding, previous studies have shown that antimicrobial peptides such as porcine b defensin 2 and Cathelicidin-BF attenuate the DSS-induced disruption of mucin expression in the intestine of mice (3,14). These data suggest that CWA modulates goblet cell function and MUC-2 production in the intestine.…”

“…Bacteria do not easily develop resistance against antimicrobial peptides because of the membrane-disrupting mechanisms of these molecules (13). Cathelicidin peptides, one family of antimicrobial peptides, not only exhibit antimicrobial activities (14) but they also function as immune regulators, thereby modulating immune responses in the host (12,15). For instance, LL-37 attracts T cells, neutrophils, mast cells, and macrophages and modulates LPSinduced inflammation by binding to LPS or directly perturbing the MyD88 signaling pathway.…”

“…Cathelicidin-WA (CWA), a novel cathelicidin peptide from snakes, has been shown to exhibit strong antimicrobial activities against Gram-negative enteric bacteria (18,19). Additionally, CWA can attenuate intestinal inflammation via immune regulation, independently of its antibacterial activity (10,14). Furthermore, in weaned piglets, CWA improves intestinal epithelial barrier function by increasing the expression of TJ proteins (10).…”

Bugging inflammation: role of the gut microbiota

“…Studies suggest that antibiotics therapy with the combined dose of ampicillin, metronidazole, neomycin and vancomycin, or bacitracin and neomycin, increases bacterial translocation, induces mild inflammation and the risk of developing DSS‐induced colitis 65 , 66 . However, different studies using CIN‐102, a natural cinnamon oil composition‐like mixture with broad‐spectrum antibacterial activity, and cathelicidin from Bungarus fasciatus decreased intestinal bacterial load, and improved symptoms of DSS‐induced colitis 67 , 68 . Ciprofloxacin and metronidazole have also been shown to reduce ileitis in genetically modified mice through the downregulation of pro‐inflammatory cytokines IFN‐γ and TNF, and T‐cell activation 69 .…”

“…65,66 However, different studies using CIN-102, a natural cinnamon oil composition-like mixture with broad-spectrum antibacterial activity, and cathelicidin from Bungarus fasciatus decreased intestinal bacterial load, and improved symptoms of DSS-induced colitis. 67,68 Ciprofloxacin and metronidazole have also been shown to reduce ileitis in genetically modified mice through the downregulation of pro-inflammatory cytokines IFN-γ and TNF, and T-cell activation. 69 Although some antibiotics such as ampicillin and ciprofloxacin have broad-spectrum activities, others have specific activities, with vancomycin targeting Gram-positive bacteria, and metronidazole targeting anaerobes.…”