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, Oct 06, 2015
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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). "
    Colitis, edited by Dr Fukuta, 01/2012: chapter Resolution of colitis-associated inflammation.; InTech., ISBN: 978-953-307-799-4
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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.
    Pharmacological Research 10/2008; 58(3-4):222-31. DOI:10.1016/j.phrs.2008.08.006 · 4.41 Impact Factor
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    • "We have recently shown that the consequence of the DSS exposure is dependent on the genetic background, and that a single DSS-provocation (dosing regime of 5 days) may, in fact lead to chronic colitis in C57BL/6 mice [10]. In this instance, the colitis is associated with marked infiltration of mono-as well as polymorphonuclear cells, irregular epithelial architecture, and increased levels of colonic pro-inflammatory cytokines and chemokines [10] [13]. Thus, the aim of this study was to validate the murine DSSinduce model using current conventional therapies for IBD patients, i.e., cyclosporine A (CsA) and methotrexate (MTX) and new biological agents (antibodies toward IL-12p40 and CD3) to evaluate the translation of mice data to human disease. "
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    ABSTRACT: Dextran sulfate sodium (DSS)-induced colitis is one of the most frequently used rodent models for inflammatory bowel disease (IBD). The aim of this study was to validate the murine DSS-induced colitis model using four therapeutic agents for IBD. C57BL/6 mice were exposed to 3% DSS for 5days followed by 7-9 days of water (acute inflammation) or 20-31 days of water (chronic phase). Clinical symptoms, plasma and colonic inflammatory markers and histology were assessed for the efficacy of cyclosporine A (CsA), methotrexate or anti-IL-12p40 in acute colitis and of anti-IL-12p40 or an agonistic anti-CD3 antibody in chronic colitis. Cyclosporine A and anti-IL-12p40 (in the acute phase) and anti-CD3 (in the chronic phase) treatment attenuated local cytokine levels, improved clinical symptoms (CsA and anti-IL-12p40) and histology (CsA and anti-CD3). Further, anti-IL-12p40 treatment was partly efficacious in the chronic phase, whereas methotrexate showed no efficacy in the acute colitis. Thus, three of the current tested agents showed efficacy in the disease model, arguing that DSS-induced colitis can be used as a relevant model for the translation of mice data to human disease.
    International Immunopharmacology 07/2008; 8(6):836-44. DOI:10.1016/j.intimp.2008.01.036 · 2.47 Impact Factor
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