Transglutaminase 2 Null Macrophages Respond To Lipopolysaccharide Stimulation By Elevated Proinflammatory Cytokine Production Due To An Enhanced Alpha(V)Beta(3) 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 beta(3) coreceptor in the engulfment process, while altered proinflammatory cytokine production is related to the lack of latent TGF beta activation by TG2 null macrophages. Here we report that TG2 null macrophages respond to lipopolysaccharide treatment by elevated IL-6 and TNF alpha production. Though TGF beta 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 TGF beta production. Instead, in the absence of TG2 integrin beta(3) maintains an elevated basal Src family kinase activity in macrophages, which leads to enhanced phosphorylation and degradation of the I kappa B alpha. Low basal levels of I kappa B alpha explain the enhanced sensitivity of TG2 null macrophages to signals that regulate NF-kappa 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. (C) 2011 Elsevier B.V. All rights reserved.