Abstract: The aim of this study was to investigate the effect of C-C Chemokine ligand 21（CCL21） on intestinal epithelial barrier tight junction protein and its mechanism.The expression profile data of 115 cases of ulcerative colitis（UC） colon tissue samples were screened in GEO database to verify the differential expression of CCL21 in UC and the protein-protein interaction（PPI） network was constructed.Human colon cancer cells HT29 were cultured in vitro and divided into a control group,CCL21 group,CCL21+ERK1/2pathway inhibitor group（CCL21+U0126 group） and CCL21+ERK1/2 pathway activator group（CCL21+C6 Ceramide group）.Western blot was used to detect the protein expression of ZO-1,occluding,claudin-1,ERK1/2 and p-ERK1/2.Real time quantitative PCR（RT-qPCR） was used to detect the mRNA expression of ZO-1,occluding and claudin-1.The tight junction structures of the control group and CCL21 group were observed by transmission electron microscopy.The results showed that CCL21 was significantly overexpressed in UC by bioinformatics analysis,and there was an interaction relationship between CCL21 and several molecules.CCL21 induced the decrease of the protein expression level and mRNA expression level of ZO-1,occluding and claudin-1（P＜0.05）,and upregulated the phosphorylation level of ERK1/2 pathway in HT29 cells（P＜0.05）.CCL21 destroyed the tight junction structure of HT29 cells,widened the gap and interrupted the continuity.U0126,an ERK1/2 inhibitor,blocked the down-regulation of the protein expression and mRNA expression of ZO-1,occluding and claudin-1 induced by CCL21（P＜0.05）.The protein and m RNA expression levels of ZO-1,occluding and claudin-1 were further down-regulated after using C6 Ceramide,an ERK1/2 activator（P＜0.05）.These results indicate that CCL21 is closely related to the pathogenesis of UC,and the ERK1/2 pathway is involved in CCL21 down-regulating the expression of tight junction proteins ZO-1,occluding and claudin-1 in HT29 cells.