Transglutaminase 2 null macrophages respond to lipopolysaccharide stimulation by elevated proinflammatory cytokine production due to an enhanced αvβ3 integrin-induced Src tyrosine kinase signaling


Transglutaminase 2 (TG2) is a protein crosslinking enzyme with several additional biochemical functions. Loss of TG2 in vivo results in impaired phagocytosis of apoptotic cells and altered proinflammatory cytokine production by macrophages engulfing apoptotic cells leading to autoimmunity. It has been proposed that TG2 acts as an integrin ß(3) coreceptor in the engulfment process, while altered proinflammatory cytokine production is related to the lack of latent TGFß activation by TG2 null macrophages. Here we report that TG2 null macrophages respond to lipopolysaccharide treatment by elevated IL-6 and TNFa production. Though TGFß has been proposed to act as a feed back regulator of proinflammatory cytokine production in LPS-stimulated macrophages, this phenomenon is not related to the lack of active TGFß production. Instead, in the absence of TG2 integrin ß(3) maintains an elevated basal Src family kinase activity in macrophages, which leads to enhanced phosphorylation and degradation of the I?Ba. Low basal levels of I?Ba explain the enhanced sensitivity of TG2 null macrophages to signals that regulate NF-?B. Our data suggest that TG2 null macrophages bear a proinflammatory phenotype, which might contribute to the enhanced susceptibility of these mice to develop autoimmunity and atherosclerosis.

Publication DOI:
Divisions: College of Health & Life Sciences > School of Biosciences
College of Health & Life Sciences > Chronic and Communicable Conditions
College of Health & Life Sciences
College of Health & Life Sciences > School of Biosciences > Cellular and Molecular Biomedicine
Aston University (General)
Additional Information: © 2011, Elsevier. Licensed under the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International
Uncontrolled Keywords: immunologic adjuvants,animals,cytokines,GTP-binding proteins,I-kappa B proteins,integrin alphaVbeta3,lipopolysaccharides,macrophages,mice,inbred C57BL mice,knockout mice,NF-kappa B,signal transduction,transforming growth factor beta,transglutaminases,src-family kinases
Publication ISSN: 1879-0542
Last Modified: 03 Jan 2024 18:58
Date Deposited: 11 Mar 2019 18:10
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Related URLs: http://www.scop ... tnerID=8YFLogxK (Scopus URL)
https://www.sci ... 0915?via%3Dihub (Publisher URL)
PURE Output Type: Article
Published Date: 2011-07
Published Online Date: 2011-03-21
Authors: Sarang, Zsolt
Köröskényi, Krisztina
Pallai, Anna
Duró, Edina
Melino, Gerry
Griffin, Martin (ORCID Profile 0000-0003-3824-306X)
Fésüs, László
Szondy, Zsuzsa



Version: Accepted Version

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