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Interplay between Th1 and Th17 effector T cell pathways in the pathogenesis of spontaneous colitis and colon cancer in the Gai2-deficient mouse
Department of Microbiology and Immunology, Institute of Biomedicine and MIVAC, Sahlgrenska Academy, Göteborg, Sweden.
Department of Bioscience, AstraZeneca, Mölndal, Sweden.
Örebro University, School of Health and Medical Sciences, Örebro University, Sweden. Department of Clinical Medicine.ORCID iD: 0000-0002-2244-9816
Department of Clinical Medicine, School of Health and Medical Sciences, Örebro University, Örebro, Sweden.
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2013 (English)In: International Immunology, ISSN 0953-8178, E-ISSN 1460-2377, Vol. 25, no 1, p. 35-44Article in journal (Refereed) Published
Abstract [en]

Gαi2-deficient mice spontaneously develop colitis. Using xMAP technology and RT-PCR, we investigated cytokine/chemokine profiles during histologically defined phases of disease: (i) no/mild, (ii) moderate, (iii) severe colitis without dysplasia/cancer and (iv) severe colitis with dysplasia/cancer, compared with age-matched wild-type (WT) littermates. Colonic dysplasia was observed in 4/11 mice and cancer in 1/11 mice with severe colitis. The histology correlated with progressive increases in colon weight/cm and spleen weight, and decreased thymus weight, all more advanced in mice with dysplasia/cancer. IL-1β, IL-6, IL-12p40, IL-17, TNF-α, CCL2 and CXCL1 protein levels in colons, but not small intestines increased with colitis progression and were significantly increased in mice with moderate and severe colitis compared with WT mice, irrespective of the absence/presence of dysplasia/cancer. CCL5 did not change during colitis progression. Colonic IL-17 transcription increased 40- to 70-fold in all stages of colitis, whereas IFN-γ mRNA was gradually up-regulated 12- to 55-fold with colitis progression, and further to 62-fold in mice with dysplasia/cancer. IL-27 mRNA increased 4- to 15-fold during the course of colitis, and colonic IL-21 transcription increased 3-fold in mice with severe colitis, both irrespective of the absence/presence of dysplasia/cancer. FoxP3 transcription was significantly enhanced (3.5-fold) in mice with moderate and severe colitis, but not in mice with dysplasia/cancer, compared with WT mice. Constrained correspondence analysis demonstrated an association between increased protein levels of TNF-α, CCL2, IL-1β, IL-6 and CXCL1 and dysplasia/cancer. In conclusion, colonic responses are dominated by a mixed T(h)1/T(h)17 phenotype, with increasing T(h)1 cytokine transcription with progression of colitis in Gαi2(-/-) mice.

Place, publisher, year, edition, pages
Oxford, United Kingdom: Oxford University Press, 2013. Vol. 25, no 1, p. 35-44
Keywords [en]
Chemokines, constrained correspondence analysis, dysplasia, inflammatory bowel disease, real-time RT–PCR
National Category
Medical and Health Sciences Gastroenterology and Hepatology
Research subject
Medicine
Identifiers
URN: urn:nbn:se:oru:diva-25590DOI: 10.1093/intimm/dxs089ISI: 000313127400004PubMedID: 22962436Scopus ID: 2-s2.0-84872130510OAI: oai:DiVA.org:oru-25590DiVA, id: diva2:548260
Funder
Swedish Research Council, 2008-4075Swedish Cancer Society, CAN 2008/591
Note

Funding Agency:

Sahlgrenska Academy 

Sahlgrenska University Hospital Foundation for Clinical research 

Swedish Society of Medicine 

Available from: 2012-08-30 Created: 2012-08-30 Last updated: 2019-03-26Bibliographically approved

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Kumawat, Ashok KumarStrid, H.Rangel, IgnacioHultgren Hörnquist, Elisabeth

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Kumawat, Ashok KumarStrid, H.Rangel, IgnacioHultgren Hörnquist, Elisabeth
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School of Health and Medical Sciences, Örebro University, SwedenSchool of Medicine, Örebro University, Sweden
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International Immunology
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