Abstract
Recent studies indicate that the CXCL12/CXCR4 interaction is involved in several inflammatory conditions. However, it is unclear whether this interaction has a role in the pathophysiology of inflammatory bowel disease (IBD). We investigated the significance of this interaction in patients with IBD and in mice with dextran sulfate sodium (DSS)-induced colitis and the effect of a CXCR4 antagonist on experimental colitis. First, we measured CXCR4 expression on peripheral T cells in patients with IBD. Furthermore, we investigated CXCR4 expression on leukocytes and CXCL12 expression in the colonic tissue of mice with DSS-induced colitis, and we evaluated the effects of a CXCR4 antagonist on DSS-induced colitis and colonic inflammation of interleukin (IL)-10 knockout (KO) mice. Colonic inflammation was assessed both clinically and histologically. Cytokine production from mesenteric lymph node cells was also examined. CXCR4 expression on peripheral T cells was significantly higher in patients with active ulcerative colitis (UC) compared with normal controls, and CXCR4 expression levels of UC patients correlated with disease activity. Both CXCR4 expression on leukocytes and CXCL12 expression in colonic tissue were significantly increased in mice with DSS-induced colitis. Administration of a CXCR4 antagonist ameliorated colonic inflammation in DSS-induced colitis and IL-10 KO mice. CXCR4 antagonist reduced tumor necrosis factor-α and interferon-γ production from mesenteric lymph node cells, whereas it did not affect IL-10 production. The percentage of mesenteric Foxp3+CD25+ T cells in DSS-induced colitis was not affected by CXCR4 antagonist. These results suggest that blockade of this chemokine axis might have potential as a therapeutic target for the treatment of IBD.
Footnotes
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This work was supported by a grant-in-aid for Scientific Research (C) from the Ministry of Culture and Science of Japan (Grant 18590677; to H.N.); grants-in-aid for Scientific Research (16017240, 16017249, 17013051, 17659212, and 18012029) from the Ministry of Education, Culture, Sports, Science and Technology of Japan; grant-in-aid for Scientific Research (15209024 and 18209027) from Japan Society for the Promotion of Science; and grant-in-aid for Research on Measures for Intractable Diseases, and Research on Advanced Medical Technology (nano005) from the Ministry of Health, Labor, and Welfare, Japan to Tsutomu Chiba.
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Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.
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doi:10.1124/jpet.108.141085.
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ABBREVIATIONS: IBD, inflammatory bowel disease; CD, Crohn's disease; UC, ulcerative colitis; DSS, dextran sulfate sodium; IL, interleukin; KO, knockout; Abs, antibodies; FACS, fluorescence-activated cell sorter; MTWSI, modified Truelove Witts severity index; GFP, green fluorescent protein; TF14016, 4-fluorobenzoylH-Arg-Arg-Nal-Cys-Tyr-Cit-Lys-d-Lys-Pro-Tyr-Arg-Cit-Cys-Arg-NH2, (S-S bridged, Nal = l-2-naphthylalanine; Cit = l-citrulline); PBS, phosphate-buffered saline; MLN, mesenteric lymph node; Gr-1, granulocyte-differentiation antigen-1; Mac-1, macrophage adhesion molecule-1; α-SMA, α-smooth muscle actin; PECAM-1, platelet endothelial cell adhesion molecule-1; rRNA, ribosomal RNA; TNF, tumor necrosis factor; IFN, interferon; Th, T helper.
- Received May 12, 2008.
- Accepted August 19, 2008.
- The American Society for Pharmacology and Experimental Therapeutics
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