173 TACE Inducer in Non-Pathogenic Intestinal Commensal Microbiota in Humans Promotes Colon Tumorigeneis via Accelerating of IL6 Trans-Signaling in Mucosal Dendritic Cells

Abstract

Background /Aim Activation of the IL6/Stat3 via IL6 trans-signaling is important for the pathogenesis of colitis-associated cancer (CAC). TNFα converting enzyme (TACE) plays an essential role in triggering the cascade of IL6 trans-signaling by cleaving of IL6Rα on the cell membrane. TCRβ/p53 double knockout mice (DKO) spontaneously develop CAC in the presence of commensal bacteria in association with the increase of TACE+ F4/80+ lamina propria dendritic cells (LPDCs) in colonic mucosa. This study was aimed to elucidate the roles of commensal bacteria in the activation of TACE in F4/80+ LPDCs and the impacts of TACE-inducing bacteria on the colon-tumorigenesis of DKO. We also examined whether the activation of IL6 trans-signaling was actually involved in the colon-tumorigenesis caused by TACE-inducer in DKO. Method First, we examined TACE mRNA expression in F4/80+ LPDC cell line (iDEC5) stimulated by 45 strains of human commensal bacteria (C. coccoides, C. leptum, C.ramosum, Bacteroides, Prevotella, Bifidobacterium, Atopobium, Enterobacteriaceae, Lactobacillus, Fusobacterium, and Staphylococcus). Second, to investigate the role of TACEinducer on the colon-tumorigenesis of DKO, we compared the incidence of CAC in gnotobiotic (GB)-DKO colonized with TACE-inducer or TACE-uninducer. Finally, we examined the effects of soluble gp130Fc fusion protein (sgp130Fc), a competitive inhibitor of IL6 trans-signaling, on the colon-tumorigenesis in GB-DKO colonized with TACE-inducer. Results Human commensal bacteria were divided into three groups based on the activities to induce TACE mRNA expression in iDEC5; high TACE-inducer, intermediate TACEinducer and TACE-uninducer. GB-DKO colonized with TACE-inducer actually suffered from CAC, whereas TACE-uninducer did not cause CAC. Moreover, the colon-tumorigenesis in GB-DKO was associated with the massive infiltration of TACE+ F4/80+ LPDCs. Treatment of sgp130Fc significantly suppressed CAC in GB-DKO and reduced the infiltration of TACE+ F4/80+ LPDCs in colonic mucosa. Moreover, TACE activity and the expression level of phospho-STAT3 in the colonic mucosa of sgp130Fc group were significantly lower than those of control group.ConclusionCollectively, these results demonstrate that TACE-inducer derived from human commensal bacteria promotes colon-tumorigenesis via activation of IL6 trans-signaling in LPDCs.