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ABIN2 Function Is Required To Suppress DSS-Induced Colitis by a Tpl2-Independent Mechanism.
- Source :
-
Journal of immunology (Baltimore, Md. : 1950) [J Immunol] 2018 Dec 01; Vol. 201 (11), pp. 3373-3382. Date of Electronic Publication: 2018 Oct 24. - Publication Year :
- 2018
-
Abstract
- The A20-binding inhibitor of NF-κB 2 (ABIN2) interacts with Met1-linked ubiquitin chains and is an integral component of the tumor progression locus 2 (Tpl2) kinase complex. We generated a knock-in mouse expressing the ubiquitin-binding-defective mutant ABIN2[D310N]. The expression of Tpl2 and its activation by TLR agonists in macrophages or by IL-1β in fibroblasts from these mice was unimpaired, indicating that the interaction of ABIN2 with ubiquitin oligomers is not required for the stability or activation of Tpl2. The ABIN2[D310N] mice displayed intestinal inflammation and hypersensitivity to dextran sodium sulfate-induced colitis, an effect that was mediated by radiation-resistant cells rather than by hematopioetic cells. The IL-1β-dependent induction of cyclooxygenase 2 (COX2) and the secretion of PGE <subscript>2</subscript> was reduced in mouse embryonic fibroblasts and intestinal myofibroblasts (IMFs) from ABIN2[D310N] mice. These observations are similar to those reported for the Tpl2 knockout (KO) mice (Roulis et al. 2014. Proc. Natl. Acad. Sci. USA 111: E4658-E4667), but the IL-1β-dependent production of COX2 and PGE <subscript>2</subscript> in mouse embryonic fibroblasts or IMFs was unaffected by pharmacological inhibition of Tpl2 in wild-type mice. The expression of ABIN2 is decreased drastically in Tpl2 KO mice. These and other lines of evidence suggest that the hypersensitivity of Tpl2 KO mice to dextran sodium sulfate-induced colitis is not caused by the loss of Tpl2 catalytic activity but by the loss of ABIN2, which impairs COX2 and PGE <subscript>2</subscript> production in IMFs by a Tpl2 kinase-independent pathway.<br /> (Copyright © 2018 by The American Association of Immunologists, Inc.)
- Subjects :
- Adaptor Proteins, Signal Transducing genetics
Animals
Cells, Cultured
Colitis chemically induced
Cyclooxygenase 2 genetics
Cyclooxygenase 2 metabolism
Dextran Sulfate
Dinoprostone metabolism
Gene Knock-In Techniques
Interleukin-1beta metabolism
MAP Kinase Kinase Kinases genetics
Mice
Mice, Knockout
Mice, Transgenic
Mutation genetics
Protein Binding genetics
Proto-Oncogene Proteins genetics
Ribonuclease, Pancreatic metabolism
Signal Transduction
Ubiquitins metabolism
Adaptor Proteins, Signal Transducing metabolism
Colitis immunology
MAP Kinase Kinase Kinases metabolism
Macrophages immunology
Myofibroblasts immunology
Proto-Oncogene Proteins metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1550-6606
- Volume :
- 201
- Issue :
- 11
- Database :
- MEDLINE
- Journal :
- Journal of immunology (Baltimore, Md. : 1950)
- Publication Type :
- Academic Journal
- Accession number :
- 30355787
- Full Text :
- https://doi.org/10.4049/jimmunol.1700614