RGD Reference Report - Knockout of Mkp-1 exacerbates colitis in Il-10-deficient mice. - Rat Genome Database

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Knockout of Mkp-1 exacerbates colitis in Il-10-deficient mice.

Authors: Matta, R  Barnard, JA  Wancket, LM  Yan, J  Xue, J  Grieves, J  Frazier, WJ  Nelin, L  Cato, AC  Liu, Y 
Citation: Matta R, etal., Am J Physiol Gastrointest Liver Physiol. 2012 Jun 1;302(11):G1322-35. doi: 10.1152/ajpgi.00018.2012. Epub 2012 Mar 29.
RGD ID: 7771532
Pubmed: PMID:22461024   (View Abstract at PubMed)
PMCID: PMC3378166   (View Article at PubMed Central)
DOI: DOI:10.1152/ajpgi.00018.2012   (Journal Full-text)

Il-10-deficient mice develop colitis associated with exaggerated Th1/Th17 responses and are a valuable model of inflammatory bowel disease. Mkp-1 is a major negative regulator of MAPKs, and its expression is enhanced by IL-10. To understand the role of Mkp-1 in the regulation of intestinal mucosal immune responses, we studied the effect of Mkp-1 deletion on the pathogenesis of colitis in Il-10(-/-) mice. We found that knockout of Mkp-1 on an Il-10(-/-) background accelerated the development of colitis. Compared with Il-10(-/-) mice, colitis not only appeared earlier but also was more severe in Il-10(-/-)/Mkp-1(-/-) mice. Il-10(-/-) mice exhibited a mild intestinal inflammation in the specific pathogen-free environment, and rectal prolapse rarely appeared before 6 mo of age. In contrast, the majority of Il-10(-/-)/Mkp-1(-/-) mice developed severe colitis rapidly and presented with rectal prolapse after only 2-3 mo. The colon of Il-10(-/-)/Mkp-1(-/-) mice showed diffuse transmural chronic inflammation and mucosal hyperplasia, with significantly more proliferating crypt epithelial cells than those of Il-10(-/-) mice. In addition to the severe colitis, Il-10(-/-)/Mkp-1(-/-) mice also developed conjunctivitis and blepharitis. The colon of Il-10(-/-)/Mkp-1(-/-) mice contained significantly higher levels of proinflammatory cytokines and exhibited greater MAPK activities than did the colon of Il-10(-/-) mice. Splenocytes and lymphocytes from Il-10(-/-)/Mkp-1(-/-) mice produced higher levels of Th1 cytokines ex vivo upon activation than did cells from Il-10(-/-) mice. Our studies support a pivotal role of Mkp-1 as a negative regulator of mucosal immune responses and highlight its protective function against inflammatory bowel disease.

RGD Manual Disease Annotations    Click to see Annotation Detail View
TermQualifierEvidenceWithReferenceNotesSourceOriginal Reference(s)
colitis severityISODusp1 (Mus musculus)7771532; 7771532 RGD 
colitis severityIGIIl10 (Mus musculus)7771532 RGD 
colitis  ISOIl10 (Mus musculus)7771532; 7771532 RGD 
colitis  IMP 7771532 RGD 

Objects Annotated

Genes (Rattus norvegicus)
Dusp1  (dual specificity phosphatase 1)
Il10  (interleukin 10)

Genes (Mus musculus)
Dusp1  (dual specificity phosphatase 1)
Il10  (interleukin 10)

Genes (Homo sapiens)
DUSP1  (dual specificity phosphatase 1)
IL10  (interleukin 10)


Additional Information