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Themis2/ICB1 Is a Signaling Scaffold That Selectively Regulates Macrophage Toll-Like Receptor Signaling and Cytokine Production

Peirce, MJ; Brook, M; Morrice, N; Snelgrove, R; Begum, S; Lanfrancotti, A; Notley, C; ... Wait, R; + view all (2010) Themis2/ICB1 Is a Signaling Scaffold That Selectively Regulates Macrophage Toll-Like Receptor Signaling and Cytokine Production. PLOS ONE , 5 (7) , Article e11465. 10.1371/journal.pone.0011465. Green open access

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Abstract

Background: Thymocyte expressed molecule involved in selection 1 (Themis1, SwissProt accession number Q8BGW0) is the recently characterised founder member of a novel family of proteins. A second member of this family, Themis2 (Q91YX0), also known as ICB1 (Induced on contact with basement membrane 1), remains unreported at the protein level despite microarray and EST databases reporting Themis2 mRNA expression in B cells and macrophages.Methodology/Principal Findings: Here we characterise Themis2 protein for the first time and show that it acts as a macrophage signalling scaffold, exerting a receptor-, mediator- and signalling pathway-specific effect on TLR responses in RAW 264.7 macrophages. Themis2 over-expression enhanced the LPS-induced production of TNF but not IL-6 or Cox-2, nor TNF production induced by ligands for TLR2 (PAM3) or TLR3 (poly I: C). Moreover, LPS-induced activation of the MAP kinases ERK and p38 was enhanced in cells over-expressing Themis2 whereas the activation of JNK, IRF3 or NF-kappa B p65, was unaffected. Depletion of Themis2 protein by RNA inteference inhibited LPS-induced TNF production in primary human macrophages demonstrating a requirement for Themis2 in this event. Themis2 was inducibly tyrosine phosphorylated upon LPS challenge and interacted with Lyn kinase (P25911), the Rho guanine nucleotide exchange factor, Vav (P27870), and the adaptor protein Grb2 (Q60631). Mutation of either tyrosine 660 or a proline-rich sequence (PPPRPPK) simultaneously interrupted this complex and reduced by approximately 50% the capacity of Themis2 to promote LPS-induced TNF production. Finally, Themis2 protein expression was induced during macrophage development from murine bone marrow precursors and was regulated by inflammatory stimuli both in vitro and in vivo.Conclusions/Significance: We hypothesise that Themis2 may constitute a novel, physiological control point in macrophage inflammatory responses.

Type: Article
Title: Themis2/ICB1 Is a Signaling Scaffold That Selectively Regulates Macrophage Toll-Like Receptor Signaling and Cytokine Production
Open access status: An open access version is available from UCL Discovery
DOI: 10.1371/journal.pone.0011465
Publisher version: http://dx.doi.org/10.1371/journal.pone.0011465
Language: English
Additional information: © 2010 Peirce et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. This work was funded by a core grant to the Kennedy Institute provided by the Arthritis Research Campaign, UK (http://www.arc.org.uk/) and by the Trustees of the Kennedy Institute. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Keywords: TUMOR-NECROSIS-FACTOR, ACTIVATED PROTEIN-KINASE, BRUTONS TYROSINE KINASE, MESSENGER-RNA STABILITY, TNF-ALPHA PRODUCTION, CANCER CELL-LINES, NF-KAPPA-B, RICH ELEMENT, POSITIVE SELECTION, MEMBRANE-PROTEINS
UCL classification: UCL
UCL > Provost and Vice Provost Offices
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences
URI: https://discovery.ucl.ac.uk/id/eprint/116291
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