Local production of chemokines and prostaglandin E2 in the acute, chronic and recovery phase of murine experimental colitis

Department of Integrative Pharmacology, AstraZeneca R&D Mölndal, GI Biology, SE-431 83, Sweden.
Cytokine (Impact Factor: 2.66). 10/2006; 35(5-6):275-83. DOI: 10.1016/j.cyto.2006.09.007
Source: PubMed


Increased levels of chemokines and prostaglandins have been reported in patients with inflammatory bowel disease, although their changes during disease development are less understood. The aim of this study was to investigate the local production of nine selected chemokines and prostaglandin E(2) (PGE(2)) to elucidate their role in colitis progression in BALB/c and C57BL/6 mice exposed to dextran sulphate sodium. The acute inflammation in both strains was accompanied by a significant up-regulation of CXCL1, CXCL2/3, CXCL10, CCL2, CCL4 and CCL22 and a downregulation of PGE(2). In the recovery phase in BALB/c, one-week post-DSS, PGE(2) levels were significantly increased with a concomitant downregulation of CXCL1, CXCL2/3, CXCL10, CCL2, and CCL4. In contrast, in C57BL/6 mice CXCL1, CXCL2/3, CXCL10, CCL2, CCL3 and CCL4 production remained high during the chronic phase, without any up-regulation of PGE(2). In addition, CCL5 was significantly increased at d26 and 33 compared to d5. Interestingly, the number of macrophages was significantly increased during the acute phase, whereas T cells were significantly increased in both the acute and chronic phase in C57BL/6 mice. Thus, our results show that chemokines are produced in a dynamic manner during colitis progression.

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Available from: Silvia Melgar
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    • "Inflammation in experimentally induced colitis is characterized by increased PGs such as PGE 2 and PGD 2 . PGD 2 (Ajuebor et al, 2000; Melgar et al, 2006) is further converted by dehydratation to 15-deoxy- 12,14 -PGJ 2 (15d-PGJ 2 ) (Monneret et al, 2002), a stable PG and putative endogenous PPAR ligand with cytoprotective and anti-inflammatory properties, and hence a new potential therapeutic target in inflammatory bowel diseases (Dubuquoy et al, 2006). 7-Hydroxy-DHEA, the innate metabolite of dehydroepiandrosterone (DHEA), is normally produced in the colon and many other tissues (Doostzadeh & Morfin, 1996; Morfin & Courchay, 1994) but overproduced by IL-1β during the inflammatory process as shown in mice and humans (Dulos et al, 2004; Dulos et al, 2005). "

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    • "Clinical symptoms in the models are body weight loss, diarrhoea, and hunched posture. The histopathological characteristics of the DSS model include distorted epithelial and crypt architecture, infiltration of neutrophils and macrophages early in disease progression accompanied by T and B cell infiltration later in the inflammation [2] [3]. Infiltration of inflammatory cells induces production of pro-inflammatory mediators, e.g. "
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    ABSTRACT: The aim of this study was to investigate the relevance of mouse ex vivo cultures as a first screening model for new therapeutic agents of Inflammatory Bowel Disease (IBD). Two murine models (dextran sodium sulphate (DSS)-induced colitis and Galphai2-deficient mice) and two anti-inflammatory agents (methyl-prednisolone and the proteasome inhibitor MG132) were evaluated. The in vivo effects of methyl-prednisolone were assessed in both models. Ex vivo colonic tissue from both mouse models were cultured in the presence or absence of the drugs and TaqMan Low-Density arrays were used to assess the regulation of inflammatory genes before and after drug treatment. Colitis induced a similar inflammatory gene profile in both mouse models in in vivo studies and in ex vivo cultures. The differences encountered reflected the different phases of colitis in the models, e.g. innate cytokine/chemokine profile in the DSS model and T cell related markers in Galphai2-deficient mice. After steroid treatment, a similar pattern of genes was suppressed in the two mouse models. We confirmed the suppression of inflammatory gene expression for IL-1beta, IL-6 and iNOS in ex vivo and in vivo colons from both mouse models by quantitative RT-PCR. Importantly, the inflammatory responses in the murine ex vivo culture system reflected the in vivo response in the inflamed colonic tissue as assessed by changes in inflammatory gene expression, suggesting that the murine culture system can be used for validation of future IBD therapies.
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    • "e early phase of DSS-induced colitis (Murano et al., 2000;Melgar et al., 2006). On the other hand, the sustained increase of CXCR4 expression on peripheral T cells at the late phase of DSS-induced colitis, as observed in the present study, suggests that T cells are involved in sustained colonic inflammation after DSS administration in C57BL/6 mice.Melgar et al. (2006)reported that only 5-day administration of DSS induces chronic inflammation of the colon in C57BL/6 mice. Taken together, the increased expression of CXCR4 on T cells might mainly contribute to the development of chronic colitis induced by DSS administration. An important finding of our study is that blocking the CXCL12/CXCR4 chemotaxis "
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    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.
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