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

Immunol Lett. 2011 Jul;138(1):71-8. doi: 10.1016/j.imlet.2011.03.004. Epub 2011 Mar 21.

Abstract

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 β(3) coreceptor in the engulfment process, while altered proinflammatory cytokine production is related to the lack of latent TGFβ activation by TG2 null macrophages. Here we report that TG2 null macrophages respond to lipopolysaccharide treatment by elevated IL-6 and TNFα production. Though TGFβ 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 TGFβ production. Instead, in the absence of TG2 integrin β(3) maintains an elevated basal Src family kinase activity in macrophages, which leads to enhanced phosphorylation and degradation of the IκBα. Low basal levels of IκBα explain the enhanced sensitivity of TG2 null macrophages to signals that regulate NF-κB. 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 types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adjuvants, Immunologic / pharmacology
  • Animals
  • Cytokines / metabolism*
  • GTP-Binding Proteins / deficiency*
  • GTP-Binding Proteins / genetics
  • GTP-Binding Proteins / metabolism
  • I-kappa B Proteins / metabolism
  • Integrin alphaVbeta3 / metabolism*
  • Lipopolysaccharides / pharmacology*
  • Macrophages* / drug effects
  • Macrophages* / enzymology
  • Macrophages* / immunology
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • NF-kappa B / metabolism
  • Signal Transduction* / drug effects
  • Transforming Growth Factor beta / metabolism
  • Transglutaminases / deficiency*
  • Transglutaminases / genetics
  • Transglutaminases / metabolism
  • src-Family Kinases / metabolism*

Substances

  • Adjuvants, Immunologic
  • Cytokines
  • I-kappa B Proteins
  • Integrin alphaVbeta3
  • Lipopolysaccharides
  • NF-kappa B
  • Transforming Growth Factor beta
  • transglutaminase 2
  • Transglutaminases
  • src-Family Kinases
  • GTP-Binding Proteins