{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,16]],"date-time":"2026-05-16T14:22:20Z","timestamp":1778941340832,"version":"3.51.4"},"reference-count":36,"publisher":"Oxford University Press (OUP)","issue":"11","license":[{"start":{"date-parts":[[2018,12,1]],"date-time":"2018-12-01T00:00:00Z","timestamp":1543622400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/pages\/standard-publication-reuse-rights"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2018,12,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>The A20-binding inhibitor of NF-\u03baB 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\u2013defective mutant ABIN2[D310N]. The expression of Tpl2 and its activation by TLR agonists in macrophages or by IL-1\u03b2 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\u2013induced colitis, an effect that was mediated by radiation-resistant cells rather than by hematopioetic cells. The IL-1\u03b2\u2013dependent induction of cyclooxygenase 2 (COX2) and the secretion of PGE2 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\u2013E4667), but the IL-1\u03b2\u2013dependent production of COX2 and PGE2 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\u2013induced colitis is not caused by the loss of Tpl2 catalytic activity but by the loss of ABIN2, which impairs COX2 and PGE2 production in IMFs by a Tpl2 kinase\u2013independent pathway.<\/jats:p>","DOI":"10.4049\/jimmunol.1700614","type":"journal-article","created":{"date-parts":[[2018,10,24]],"date-time":"2018-10-24T14:58:39Z","timestamp":1540393119000},"page":"3373-3382","source":"Crossref","is-referenced-by-count":10,"title":["ABIN2 Function Is Required To Suppress DSS-Induced Colitis by a Tpl2-Independent Mechanism"],"prefix":"10.1093","volume":"201","author":[{"given":"Sambit K","family":"Nanda","sequence":"first","affiliation":[{"name":"Medical Research Council Protein Phosphorylation and Ubiquitylation Unit, University of Dundee , Dundee DD1 5EH ,","place":["United Kingdom"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tsunehisa","family":"Nagamori","sequence":"additional","affiliation":[{"name":"Medical Research Council Protein Phosphorylation and Ubiquitylation Unit, University of Dundee , Dundee DD1 5EH ,","place":["United Kingdom"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mark","family":"Windheim","sequence":"additional","affiliation":[{"name":"Medical Research Council Protein Phosphorylation and Ubiquitylation Unit, University of Dundee , Dundee DD1 5EH ,","place":["United Kingdom"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sylvia","family":"Amu","sequence":"additional","affiliation":[{"name":"Trinity Biomedical Sciences Institute, School of Medicine, Trinity College Dublin , Dublin 2 ,","place":["Ireland"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Gabriella","family":"Aviello","sequence":"additional","affiliation":[{"name":"Trinity Biomedical Sciences Institute, School of Medicine, Trinity College Dublin , Dublin 2 ,","place":["Ireland"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9094-1263","authenticated-orcid":false,"given":"Janet","family":"Patterson-Kane","sequence":"additional","affiliation":[{"name":"School of Veterinary Medicine, University of Glasgow , Glasgow G61 1QH ,","place":["United Kingdom"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"J Simon C","family":"Arthur","sequence":"additional","affiliation":[{"name":"Division of Cell Signalling and Immunology, School of Life Sciences, University of Dundee , Dundee DD1 5EH ,","place":["United Kingdom"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Steven C","family":"Ley","sequence":"additional","affiliation":[{"name":"The Francis Crick Institute , London NW1 1AT ,","place":["United Kingdom"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8401-7293","authenticated-orcid":false,"given":"Padraic","family":"Fallon","sequence":"additional","affiliation":[{"name":"Trinity Biomedical Sciences Institute, School of Medicine, Trinity College Dublin , Dublin 2 ,","place":["Ireland"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Philip","family":"Cohen","sequence":"additional","affiliation":[{"name":"Medical Research Council Protein Phosphorylation and Ubiquitylation Unit, University of Dundee , Dundee DD1 5EH ,","place":["United Kingdom"]}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"286","published-online":{"date-parts":[[2018,12,1]]},"reference":[{"key":"2025030417575199400_r1","doi-asserted-by":"crossref","first-page":"5235","DOI":"10.1128\/MCB.24.12.5235-5248.2004","article-title":"ABIN-2 forms a ternary complex with TPL-2 and NF-kappa B1 p105 and is essential for TPL-2 protein stability","volume":"24","author":"Lang","year":"2004","journal-title":"Mol. Cell. Biol."},{"key":"2025030417575199400_r2","doi-asserted-by":"crossref","first-page":"679","DOI":"10.1038\/nri3495","article-title":"Mitogen-activated protein kinases in innate immunity","volume":"13","author":"Arthur","year":"2013","journal-title":"Nat. Rev. Immunol."},{"key":"2025030417575199400_r3","doi-asserted-by":"crossref","first-page":"6040","DOI":"10.1128\/MCB.24.13.6040-6048.2004","article-title":"IkappaB kinase is an essential component of the Tpl2 signaling pathway","volume":"24","author":"Waterfield","year":"2004","journal-title":"Mol. Cell. Biol."},{"key":"2025030417575199400_r4","doi-asserted-by":"crossref","first-page":"2350","DOI":"10.1073\/pnas.0409856102","article-title":"Phosphorylation at Thr-290 regulates Tpl2 binding to NF-kappaB1\/p105 and Tpl2 activation and degradation by lipopolysaccharide","volume":"102","author":"Cho","year":"2005","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"2025030417575199400_r5","doi-asserted-by":"crossref","first-page":"E2394","DOI":"10.1073\/pnas.1320440111","article-title":"I\u03baB kinase-induced interaction of TPL-2 kinase with 14-3-3 is essential for Toll-like receptor activation of ERK-1 and -2 MAP kinases","volume":"111","author":"Ben-Addi","year":"2014","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"2025030417575199400_r6","doi-asserted-by":"crossref","first-page":"1071","DOI":"10.1016\/S0092-8674(00)00210-5","article-title":"TNF-alpha induction by LPS is regulated posttranscriptionally via a Tpl2\/ERK-dependent pathway","volume":"103","author":"Dumitru","year":"2000","journal-title":"Cell"},{"key":"2025030417575199400_r7","doi-asserted-by":"crossref","first-page":"2845","DOI":"10.1042\/BCJ20160502","article-title":"TLR and TNF-R1 activation of the MKK3\/MKK6-p38\u03b1 axis in macrophages is mediated by TPL-2 kinase","volume":"473","author":"Pattison","year":"2016","journal-title":"Biochem. J."},{"key":"2025030417575199400_r8","doi-asserted-by":"crossref","first-page":"eaah4273","DOI":"10.1126\/scisignal.aah4273","article-title":"The kinase TPL2 activates ERK and p38 signaling to promote neutrophilic inflammation","volume":"10","author":"Senger","year":"2017","journal-title":"Sci. Signal"},{"key":"2025030417575199400_r9","doi-asserted-by":"crossref","first-page":"149","DOI":"10.1242\/jcs.018671","article-title":"TPL2-mediated activation of ERK1 and ERK2 regulates the processing of pre-TNF alpha in LPS-stimulated macrophages","volume":"121","author":"Rousseau","year":"2008","journal-title":"J. Cell Sci."},{"key":"2025030417575199400_r10","doi-asserted-by":"crossref","first-page":"1732","DOI":"10.4049\/jimmunol.1300146","article-title":"TPL-2-ERK1\/2 signaling promotes host resistance against intracellular bacterial infection by negative regulation of type I IFN production","volume":"191","author":"McNab","year":"2013","journal-title":"J. Immunol."},{"key":"2025030417575199400_r11","doi-asserted-by":"crossref","first-page":"1563","DOI":"10.1084\/jem.20020281","article-title":"Genetic dissection of the cellular pathways and signaling mechanisms in modeled tumor necrosis factor-induced Crohn\u2019s-like inflammatory bowel disease","volume":"196","author":"Kontoyiannis","year":"2002","journal-title":"J. Exp. Med."},{"key":"2025030417575199400_r12","doi-asserted-by":"crossref","first-page":"119","DOI":"10.1038\/nature11582","article-title":"Host-microbe interactions have shaped the genetic architecture of inflammatory bowel disease","volume":"491","author":"Jostins","year":"2012","journal-title":"Nature"},{"key":"2025030417575199400_r13","doi-asserted-by":"crossref","first-page":"1799","DOI":"10.1136\/gutjnl-2014-308922","article-title":"A TPL2 (MAP3K8) disease-risk polymorphism increases TPL2 expression thereby leading to increased pattern recognition receptor-initiated caspase-1 and caspase-8 activation, signalling and cytokine secretion","volume":"65","author":"Hedl","year":"2016","journal-title":"Gut"},{"key":"2025030417575199400_r14","doi-asserted-by":"crossref","first-page":"E4658","DOI":"10.1073\/pnas.1415762111","article-title":"Intestinal myofibroblast-specific Tpl2-Cox-2-PGE2 pathway links innate sensing to epithelial homeostasis","volume":"111","author":"Roulis","year":"2014","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"2025030417575199400_r15","doi-asserted-by":"crossref","first-page":"685","DOI":"10.1016\/S1097-2765(03)00070-4","article-title":"NF-kappaB1\/p105 regulates lipopolysaccharide-stimulated MAP kinase signaling by governing the stability and function of the Tpl2 kinase","volume":"11","author":"Waterfield","year":"2003","journal-title":"Mol. Cell"},{"key":"2025030417575199400_r16","doi-asserted-by":"crossref","first-page":"4739","DOI":"10.1128\/MCB.23.14.4739-4752.2003","article-title":"NF-kappaB1 p105 negatively regulates TPL-2 MEK kinase activity","volume":"23","author":"Beinke","year":"2003","journal-title":"Mol. Cell. Biol."},{"key":"2025030417575199400_r17","doi-asserted-by":"crossref","first-page":"606","DOI":"10.1038\/ni1334","article-title":"ABIN-2 is required for optimal activation of Erk MAP kinase in innate immune responses","volume":"7","author":"Papoutsopoulou","year":"2006","journal-title":"Nat. Immunol."},{"key":"2025030417575199400_r18","doi-asserted-by":"crossref","first-page":"3518","DOI":"10.4049\/jimmunol.1300172","article-title":"Regulation of experimental autoimmune encephalomyelitis by TPL-2 kinase","volume":"192","author":"Sriskantharajah","year":"2014","journal-title":"J. Immunol."},{"key":"2025030417575199400_r19","doi-asserted-by":"crossref","first-page":"7355","DOI":"10.1128\/MCB.00301-07","article-title":"Phosphorylation of TPL-2 on serine 400 is essential for lipopolysaccharide activation of extracellular signal-regulated kinase in macrophages","volume":"27","author":"Robinson","year":"2007","journal-title":"Mol. Cell. Biol."},{"key":"2025030417575199400_r20","doi-asserted-by":"crossref","first-page":"1783","DOI":"10.1128\/MCB.02380-06","article-title":"Interleukin-1 (IL-1) induces the Lys63-linked polyubiquitination of IL-1 receptor-associated kinase 1 to facilitate NEMO binding and the activation of IkappaBalpha kinase","volume":"28","author":"Windheim","year":"2008","journal-title":"Mol. Cell. Biol."},{"key":"2025030417575199400_r21","doi-asserted-by":"crossref","first-page":"2717","DOI":"10.4049\/jimmunol.1203268","article-title":"Two phases of inflammatory mediator production defined by the study of IRAK2 and IRAK1 knock-in mice","volume":"191","author":"Pauls","year":"2013","journal-title":"J. Immunol."},{"key":"2025030417575199400_r22","doi-asserted-by":"crossref","first-page":"35663","DOI":"10.1074\/jbc.M111.267567","article-title":"Polyubiquitin binding to optineurin is required for optimal activation of TANK-binding kinase 1 and production of interferon \u03b2","volume":"286","author":"Gleason","year":"2011","journal-title":"J. Biol. Chem."},{"key":"2025030417575199400_r23","doi-asserted-by":"crossref","first-page":"2871","DOI":"10.1128\/MCB.22.8.2871-2881.2002","article-title":"MSK1 and MSK2 are required for the mitogen- and stress-induced phosphorylation of CREB and ATF1 in fibroblasts","volume":"22","author":"Wiggin","year":"2002","journal-title":"Mol. Cell. Biol."},{"key":"2025030417575199400_r24","doi-asserted-by":"crossref","first-page":"1215","DOI":"10.1084\/jem.20102177","article-title":"Polyubiquitin binding to ABIN1 is required to prevent autoimmunity","volume":"208","author":"Nanda","year":"2011","journal-title":"J. Exp. Med."},{"key":"2025030417575199400_r25","doi-asserted-by":"crossref","first-page":"3739","DOI":"10.1038\/sj.onc.1211042","article-title":"Ubiquitin binding mediates the NF-kappaB inhibitory potential of ABIN proteins","volume":"27","author":"Wagner","year":"2008","journal-title":"Oncogene"},{"key":"2025030417575199400_r26","doi-asserted-by":"crossref","first-page":"15247","DOI":"10.1073\/pnas.1314715110","article-title":"Activation of the canonical IKK complex by K63\/M1-linked hybrid ubiquitin chains","volume":"110","author":"Emmerich","year":"2013","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"2025030417575199400_r27","doi-asserted-by":"crossref","first-page":"466","DOI":"10.1038\/embor.2009.55","article-title":"Molecular discrimination of structurally equivalent Lys 63-linked and linear polyubiquitin chains","volume":"10","author":"Komander","year":"2009","journal-title":"EMBO Rep."},{"key":"2025030417575199400_r28","doi-asserted-by":"crossref","first-page":"1098","DOI":"10.1016\/j.cell.2009.03.007","article-title":"Specific recognition of linear ubiquitin chains by NEMO is important for NF-kappaB activation","volume":"136","author":"Rahighi","year":"2009","journal-title":"Cell"},{"key":"2025030417575199400_r29","doi-asserted-by":"crossref","first-page":"6067","DOI":"10.1016\/j.bmcl.2006.08.102","article-title":"Inhibition of Tpl2 kinase and TNFalpha production with quinoline-3-carbonitriles for the treatment of rheumatoid arthritis","volume":"16","author":"Hu","year":"2006","journal-title":"Bioorg. Med. Chem. Lett."},{"key":"2025030417575199400_r30","doi-asserted-by":"crossref","first-page":"137","DOI":"10.1538\/expanim.48.137","article-title":"Changes in colonic mucosal permeability in mouse colitis induced with dextran sulfate sodium","volume":"48","author":"Kitajima","year":"1999","journal-title":"Exp. Anim."},{"key":"2025030417575199400_r31","doi-asserted-by":"crossref","first-page":"229","DOI":"10.1016\/j.cell.2004.07.002","article-title":"Recognition of commensal microflora by toll-like receptors is required for intestinal homeostasis","volume":"118","author":"Rakoff-Nahoum","year":"2004","journal-title":"Cell"},{"key":"2025030417575199400_r32","doi-asserted-by":"crossref","first-page":"694","DOI":"10.1016\/0016-5085(90)90290-H","article-title":"A novel method in the induction of reliable experimental acute and chronic ulcerative colitis in mice","volume":"98","author":"Okayasu","year":"1990","journal-title":"Gastroenterology"},{"key":"2025030417575199400_r33","doi-asserted-by":"crossref","first-page":"4831","DOI":"10.1093\/emboj\/cdf478","article-title":"Induction of COX-2 by LPS in macrophages is regulated by Tpl2-dependent CREB activation signals","volume":"21","author":"Eliopoulos","year":"2002","journal-title":"EMBO J."},{"key":"2025030417575199400_r34","first-page":"242","article-title":"An LKB1-interacting protein negatively regulates TNFalpha-induced NF-kappaB activation","volume":"10","author":"Liu","year":"2003","journal-title":"J. Biomed. Sci."},{"key":"2025030417575199400_r35","doi-asserted-by":"crossref","first-page":"32277","DOI":"10.1074\/jbc.M111.236448","article-title":"A20-binding inhibitor of nuclear factor-kappaB (NF-kappaB)-2 (ABIN-2) is an activator of inhibitor of NF-kappaB (IkappaB) kinase alpha (IKKalpha)-mediated NF-kappaB transcriptional activity","volume":"286","author":"Leotoing","year":"2011","journal-title":"J. Biol. Chem."},{"key":"2025030417575199400_r36","doi-asserted-by":"crossref","first-page":"630","DOI":"10.1161\/01.RES.0000063422.38690.DC","article-title":"The antiinflammatory endothelial tyrosine kinase Tie2 interacts with a novel nuclear factor-kappaB inhibitor ABIN-2","volume":"92","author":"Hughes","year":"2003","journal-title":"Circ. Res."}],"container-title":["The Journal of Immunology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/academic.oup.com\/jimmunol\/article-pdf\/201\/11\/3373\/61431198\/ji1700614.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/jimmunol\/article-pdf\/201\/11\/3373\/61431198\/ji1700614.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,3,4]],"date-time":"2025-03-04T19:29:04Z","timestamp":1741116544000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/jimmunol\/article\/201\/11\/3373\/7953457"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2018,12,1]]},"references-count":36,"journal-issue":{"issue":"11","published-print":{"date-parts":[[2018,12,1]]}},"URL":"https:\/\/doi.org\/10.4049\/jimmunol.1700614","relation":{},"ISSN":["0022-1767","1550-6606"],"issn-type":[{"value":"0022-1767","type":"print"},{"value":"1550-6606","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2018,12]]},"published":{"date-parts":[[2018,12,1]]}}}