We previously reported that syndecan‐2 expression is increased on the colonic epithelium during chronic inflammation. Here, we report that syndecan‐2 exhibits a different pattern of site‐specific colonic expression during acute inflammation. Syndecan‐2 expression was up‐regulated predominantly in the proximal colon of dextran sulfate sodium‐induced colitis mice. The colitis‐associated up‐regulation of syndecan‐2 was barely detected in Rag‐1−/− (recombination activating gene 1 knockout) mice under colitis‐inducing conditions. Increased syndecan‐2 expression correlated with increased levels of infiltrated CD4+IL‐17A+ T cells in the proximal colon. Serum levels of IL‐17A were increased during the acute inflammatory response in normal mice but not Rag‐1−/− mice. IL‐17A directly induced IL‐17 receptor (IL‐17RA) and syndecan‐2 expression in ex vivo‐cultured proximal colon tissues and adenoma cell lines from proximal colon. IL‐17RA knockdown reduced the IL‐17A‐mediated syndecan‐2 expression in SNU1235 cells. No elevation of syndecan‐2 or IL‐17RA was observed in colonic tissues from IL‐17A−/− mice during colitis induction. Finally, increased expression of syndecan‐2 and IL‐17RA was observed in the proximal colons of cecal ligation and puncture‐induced sepsis mice and infectious pan colitis patients. Together, these data suggest that acute inflammation induces syndecan‐2 expression predominantly in the proximal colon via IL‐17A‐IL‐17RA signaling during the early stage of the inflammatory response and that proximal colonic syndecan‐2 might be a biomarker for acute inflammation.—Hong, H., Song, H.‐K., Hwang, E. S., Lee, A. R., Han, D. S., Kim, S.‐E., Oh, E.‐S. Up‐regulation of syndecan‐2 in proximal colon correlates with acute inflammation. FASEB J. 33, 11381–11395 (2019). http://www.fasebj.org