ABIN2 Function Is Required To Suppress DSS-Induced Colitis by a Tpl2-Independent Mechanism

Sambit K. Nanda, Tsunehisa Nagamori, Mark Windheim, Sylvia Amu, Gabriella Aviello, Janet Patterson-Kane, J. Simon C. Arthur, Steven C. Ley, Padraic Fallon, Philip Cohen (Lead / Corresponding author)

Research output: Contribution to journalArticle

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 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-E4667), but the IL-1β-dependent 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-induced 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-independent pathway.

LanguageEnglish
Pages3373-3382
Number of pages10
JournalJournal of Immunology
Volume201
Issue number11
Early online date24 Oct 2018
DOIs
Publication statusPublished - 1 Dec 2018

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Colitis
Neoplasms
Myofibroblasts
Cyclooxygenase 2
Ubiquitin
Dinoprostone
Knockout Mice
Dextran Sulfate
Fibroblasts
Hypersensitivity
Phosphotransferases
Macrophages
Pharmacology
Radiation
Inflammation

Cite this

Nanda, Sambit K. ; Nagamori, Tsunehisa ; Windheim, Mark ; Amu, Sylvia ; Aviello, Gabriella ; Patterson-Kane, Janet ; Arthur, J. Simon C. ; Ley, Steven C. ; Fallon, Padraic ; Cohen, Philip. / ABIN2 Function Is Required To Suppress DSS-Induced Colitis by a Tpl2-Independent Mechanism. In: Journal of Immunology. 2018 ; Vol. 201, No. 11. pp. 3373-3382.
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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 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-E4667), but the IL-1β-dependent 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-induced 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-independent pathway.",
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Nanda, SK, Nagamori, T, Windheim, M, Amu, S, Aviello, G, Patterson-Kane, J, Arthur, JSC, Ley, SC, Fallon, P & Cohen, P 2018, 'ABIN2 Function Is Required To Suppress DSS-Induced Colitis by a Tpl2-Independent Mechanism' Journal of Immunology, vol. 201, no. 11, pp. 3373-3382. https://doi.org/10.4049/jimmunol.1700614

ABIN2 Function Is Required To Suppress DSS-Induced Colitis by a Tpl2-Independent Mechanism. / Nanda, Sambit K.; Nagamori, Tsunehisa; Windheim, Mark; Amu, Sylvia; Aviello, Gabriella; Patterson-Kane, Janet; Arthur, J. Simon C.; Ley, Steven C.; Fallon, Padraic; Cohen, Philip (Lead / Corresponding author).

In: Journal of Immunology, Vol. 201, No. 11, 01.12.2018, p. 3373-3382.

Research output: Contribution to journalArticle

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T1 - ABIN2 Function Is Required To Suppress DSS-Induced Colitis by a Tpl2-Independent Mechanism

AU - Nanda, Sambit K.

AU - Nagamori, Tsunehisa

AU - Windheim, Mark

AU - Amu, Sylvia

AU - Aviello, Gabriella

AU - Patterson-Kane, Janet

AU - Arthur, J. Simon C.

AU - Ley, Steven C.

AU - Fallon, Padraic

AU - Cohen, Philip

N1 - Copyright © 2018 by The American Association of Immunologists, Inc.

PY - 2018/12/1

Y1 - 2018/12/1

N2 - 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 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-E4667), but the IL-1β-dependent 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-induced 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-independent pathway.

AB - 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 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-E4667), but the IL-1β-dependent 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-induced 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-independent pathway.

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