title: Blockade of CXCL12/CXCR4 axis ameliorates murine experimental colitis.
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-alpha and interferon-gamma 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.
authors: Department of Gastroenterology and Hepatology, Graduate School of Medicine, Kyoto University, 54 Shogoin Kawahara-Cho, Sakyoku, Kyoto 606-8507, Japan. hiropy_n@kuhp.kyoto-u.ac.jp.
authors: Sakae
authors: S
authors: Mikami
authors: Hiroshi
authors: H
authors: Nakase
authors: Shuji
authors: S
authors: Yamamoto
authors: Yasuhiro
authors: Y
authors: Takeda
authors: Takuya
authors: T
authors: Yoshino
authors: Katushiro
authors: K
authors: Kasahara
authors: Satoru
authors: S
authors: Ueno
authors: Norimitsu
authors: N
authors: Uza
authors: Shinya
authors: S
authors: Oishi
authors: Nobutaka
authors: N
authors: Fujii
authors: Takashi
authors: T
authors: Nagasawa
authors: Tsutomu
authors: T
authors: Chiba
mesh_terms: D000818:Animals; D002465:Cell Movement; D054377:Chemokine CXCL12 / Q000032:analysis / Q000037:antagonists & inhibitors* / Q000502:physiology; D003092:Colitis / Q000139:chemically induced / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D003106:Colon / Q000473:pathology; D016264:Dextran Sulfate / Q000633:toxicity; D005260:Female; D051858:Forkhead Transcription Factors / Q000502:physiology; D006801:Humans; D015212:Inflammatory Bowel Diseases / Q000188:drug therapy*; D016753:Interleukin-10 / Q000502:physiology; D007962:Leukocytes / Q000502:physiology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D019718:Receptors, CXCR4 / Q000037:antagonists & inhibitors* / Q000097:blood / Q000502:physiology; D050378:T-Lymphocytes, Regulatory / Q000737:chemistry / Q000502:physiology
chemical_list: D054377:Chemokine CXCL12; D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D019718:Receptors, CXCR4; D016753:Interleukin-10; D016264:Dextran Sulfate