Transglutaminase Type II Plays a Protective Role in Hepatic Injury

Nardacci, Roberta; Iacono, Oreste Lo; Ciccosanti, Fabiola; Falasca, Laura; Addesso, Maria; Amendola, Alessandra; Antonucci, Giorgio; Craxı̀, Antonio; Fimia, Gian María; Iadevaia, Valentina; Melino, Gerry; Ruco, Luigi; Tocci, Guido; Ippolito, Giuseppe; Piacentini, Mauro

doi:10.1016/s0002-9440(10)63925-9

Cited by 65 publications

(61 citation statements)

References 40 publications

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“…AA, arachidonic acid; iNOS, inducible isoform of nitric oxide synthase; iPs, isoprostanes; PGH 2 , prostaglandin H 2 ; PL, phospholipid; PPAR␥, peroxisome proliferator-activated receptor-␥; TGF-␤, transforming growth factor-␤; TLR4, Toll-like receptor 4. injury plays a protective or pathological role. Consistent with a protective role for TG2 in liver damage, treatment of C57BL/6 TG2-deficient mice with the hepatotoxin carbon tetrachloride resulted in an increased incidence of death postinjury, relative to control C57BL/6 mice, an effect associated with an increased inflammatory response and increased ECM accumulation (204). In contrast, consistent with a proapoptotic role for TG2 is the finding that compared with their wild-type mixed-strain (SVJ129-C57BL/6) littermates, apoptosis of hepatocytes from TG2 Ϫ/Ϫ mice was markedly reduced following treatment of isolated hepatocytes with ethanol or treatment of animals with a low dose (0.1 g/g body wt) of the anti-Fas antibody Jo2, which is a known, potent inducer of endothelial cell and hepatocyte apoptosis that contributes to alcohol-induced liver damage (281).…”

Section: Hepatic and Renal Injurymentioning

confidence: 66%

“…TG2 enhances NFB activation and, thus, inflammation in microglial cells, by cross-linking IB␣, which also results in NFB dissociation and nuclear translocation (157). Increased TG2 expression, resulting from increased binding of NFB to the Tgm2 promoter, enhances extracellular TG2 cross-linking activity, a response observed in experimentally induced hepatic fibrogenesis in rats (189) and in patients with hepatic disease, who have increased ECM TG2 levels (204,222). TG2 expression is also enhanced in cartilage tissue by interleukin (IL)-1 (129) and in liver cells by IL-6 (274).…”

Section: Expression Of Tg2 and Inflammatory Mediatorsmentioning

confidence: 99%

“…Systems that have been studied include clearance of necrotic (204) or apoptotic (85) C57BL/6 TG2 ϩ/ϩ and TG2 Ϫ/Ϫ cells after hepatotoxin exposure, clearance of apoptotic cells (background strains of TG2 ϩ/ϩ and TG2 Ϫ/Ϫ mice not stated) during induced thymic involution (277), and clearance of apoptotic 94% C57BL/6 -6% SVJ129 TG2 ϩ/ϩ and TG2 Ϫ/Ϫ neutrophils during goutlike peritoneal inflammation (234). This defect was associated with the development of autoimmunity in aged mice (277).…”

Section: Phagocytosismentioning

confidence: 99%

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Transglutaminases and Disease: Lessons From Genetically Engineered Mouse Models and Inherited Disorders

Iismaa¹,

Mearns²,

Lóránd³

et al. 2009

Physiological Reviews

305

336

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The human transglutaminase (TG) family consists of a structural protein, protein 4.2, that lacks catalytic activity, and eight zymogens/enzymes, designated factor XIII-A (FXIII-A) and TG1-7, that catalyze three types of posttranslational modification reactions: transamidation, esterification, and hydrolysis. These reactions are essential for biological processes such as blood coagulation, skin barrier formation, and extracellular matrix assembly but can also contribute to the pathophysiology of various inflammatory, autoimmune, and degenerative conditions. Some members of the TG family, for example, TG2, can participate in biological processes through actions unrelated to transamidase catalytic activity. We present here a comprehensive review of recent insights into the physiology and pathophysiology of TG family members that have come from studies of genetically engineered mouse models and/or inherited disorders. The review focuses on FXIII-A, TG1, TG2, TG5, and protein 4.2, as mice deficient in TG3, TG4, TG6, or TG7 have not yet been reported, nor have mutations in these proteins been linked to human disease.

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Section: Hepatic and Renal Injurymentioning

confidence: 66%

Section: Expression Of Tg2 and Inflammatory Mediatorsmentioning

confidence: 99%

Section: Phagocytosismentioning

confidence: 99%

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Transglutaminases and Disease: Lessons From Genetically Engineered Mouse Models and Inherited Disorders

Iismaa¹,

Mearns²,

Lóránd³

et al. 2009

Physiological Reviews

305

336

View full text Add to dashboard Cite

show abstract

“…34 The TG2-null liver treated with CCl 4 fails to clear the necrotic tissue and exhibits a progressive accumulation of ECM with an elevated number of both activated hepatic stellate cells and inflammatory cells, suggesting a protective role for TG2 in liver injury. 35 Thus, both FXIII and TG2 are apparently involved in adult tissue injury and remodeling, 25 and the precise contribution of each molecule to these processes needs to be defined.…”

Section: Discussionmentioning

confidence: 99%

Critical Role of Factor XIII in the Initial Stages of Carbon Tetrachloride–Induced Adult Liver Remodeling

Tsujimoto

Moriya

Sakai

et al. 2011

The American Journal of Pathology

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The transglutaminase-mediated, covalent cross-linking of proteins is an essential step in tissue remodeling after injury. This process provides tissues with extra rigidity and resistance against proteolytic degradation. Plasma coagulation factor XIII (FXIII) is a transglutaminase that promotes cross-linking of the extracellular matrix (ECM) components fibrin and fibronectin to form a provisional matrix in response to tissue damage. However, the functional requirement for this FXIII-mediated cross-linked provisional matrix in adult tissue remodeling remains to be defined. Although it has been proposed that the formation FXIII-mediated fibrin-fibronectin provisional matrix is a critical step for ECM remodeling, we show in an FXIII subunit A-deficient murine model of acute liver injury that the lack of FXIII subunit A did not interfere with collagen reconstruction and resolution after liver injury. Furthermore, FXIIIA deficiency caused significantly increased hepatocyte apoptosis and a delay in hepatocyte regeneration after injury, which were accompanied by a significantly high induction of p53 expression. These findings suggest novel functions of FXIII that the FXIII-mediated covalently crosslinked matrix could promote survival signals for hepatocytes in adult tissue remodeling. Covalent cross-linking between proteins, including in the provisional matrix, is catalyzed by transglutaminases (TGs). This is an important process for tissue remodeling as it generates extra rigidity and a resistance against proteolytic degradation. 1 Plasma coagulation factor Xlll (FXlll), one of the TG family members, circulates as a heterotetramer composed of two catalytic A subunits (FXIII A) and two noncatalytic B subunits (FXIII B) (A 2 B 2 ), which are activated by thrombinmediated cleavage. FXlll is a Ca 2ϩ -dependent TG and catalyzes the formation of -(␥-glutamyl) lysyl crosslinks between specific protein pairs. The cross-linking of fibrin molecules by FXIII to form ␥-chain dimerization is the final step of blood coagulation. 2-4 FXIII also acts on fibronectin-fibronectin and fibrin-fibronectin cross-linking. 5,6 Thus, the action of FXIII in forming covalent crosslinkages clearly plays a vital role in establishing the mechanical stability of the clot, which is critical for homeostatic functions. 2,4 Growing evidence demonstrates that the source of FXIII is not only from plasma: Megakaryocytes/ platelets and monocytes/macrophages also contain cellular FXIII subunit A in their cytoplasm. 7,8 Acute liver injury mediated by the hepatitis virus or hepatotoxins causes massive hepatocyte apoptosis and/or fatal liver damage, and eventually liver transplantation is required. 9,10 Identification of hepatic survival factors is critical for successful therapeutic intervention in liver failure. After acute injury, the liver undergoes a wound-healing response to restore tissue architecture and maintain homeostasis. 11 It requires both a well-orchestrated proliferation of cells and the reconstruction of the extracellular matrix (ECM). A central...

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“…The absence of TG2 could be an advantage during endotoxic shock because this deficiency appears to be associated with an activation of NF-B that is transient, thus allowing the restoration of immunological equilibrium. In this context, studies from the TG2 Ϫ/Ϫ knock-out mice revealed that TG2 offers a protection against liver injuries caused by CCl 4 (36,37). Although many reports have shown an association between the levels of TG2 during inflammatory diseases, its regulation and its role in inflammatory process remain poorly understood.…”

Section: Resultsmentioning

confidence: 99%

MTA1 Coregulation of Transglutaminase 2 Expression and Function during Inflammatory Response

Ghanta¹,

Pakala²,

Reddy

et al. 2011

Journal of Biological Chemistry

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Although both metastatic tumor antigen 1 (MTA1), a master chromatin modifier, and transglutaminase 2 (TG2), a multifunctional enzyme, are known to be activated during inflammation, it remains unknown whether these molecules regulate inflammatory response in a coordinated manner. Here we investigated the role of MTA1 in the regulation of TG2 expression in bacterial lipopolysaccharide (LPS)-stimulated mammalian cells. While studying the impact of MTA1 status on global gene expression, we unexpectedly discovered that MTA1 depletion impairs the basal as well as the LPS-induced expression of TG2 in multiple experimental systems. We found that TG2 is a chromatin target of MTA1 and of NF-B signaling in LPSstimulated cells. In addition, LPS-mediated stimulation of TG2 expression is accompanied by the enhanced recruitment of MTA1, p65RelA, and RNA polymerase II to the NF-B consensus sites in the TG2 promoter. Interestingly, both the recruitment of p65 and TG2 expression are effectively blocked by a pharmacological inhibitor of the NF-B pathway. These findings reveal an obligatory coregulatory role of MTA1 in the regulation of TG2 expression and of the MTA1-TG2 pathway, at least in part, in LPS modulation of the NF-B signaling in stimulated macrophages.Inflammation is an adaptive immune response triggered by the body against detrimental stimuli and conditions such as microbial infection and tissue injury (1, 2). Inflammation is usually a healing response, but it becomes detrimental if targeted destruction and assisted repair are not properly activated (3). Primarily, macrophages and mast cells recognize the infection and produce a wide variety of inflammatory mediators such as chemokines, cytokines, etc., all contributing to the elicitation of an inflammatory response (1). The inflammatory response is characterized by coordinated regulation of signaling pathways that regulate the expression of both the pro-inflammatory and the anti-inflammatory cytokines including IL-1, IL-6, TNF-␣, receptor activator of NF-B ligand (RANKL), etc. (4). The inability of host to regulate inflammatory response results in sepsis, organ dysfunction, and even death (5). These inflammatory cytokines are under the tight control of master gene transcriptional factor NF-B in promoting the inflammation, and in turn, innate immunity (6). Furthermore, transcriptional control of such NF-B genomic targets is also under a tight control of nucleosome-remodeling coregulators and complexes, leading to either the stimulation or the repression of gene transcription at the molecular level (7-10).In recent times, metastatic tumor antigen 1 (MTA1) 3 has been recognized as one of the major coregulators in mammalian cells. MTA1 is a ubiquitously expressed chromatin modifier, having an integral role in nucleosome-remodeling and histone deacetylase (NuRD) complexes (11). MTA1 is widely up-regulated in a wide variety of human tumors and has been shown to play a role in tumorigenesis (11-14). MTA1 regulates transcription of its targets by modifying the acetylation stat...

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Transglutaminase Type II Plays a Protective Role in Hepatic Injury

Cited by 65 publications

References 40 publications

Transglutaminases and Disease: Lessons From Genetically Engineered Mouse Models and Inherited Disorders

Transglutaminases and Disease: Lessons From Genetically Engineered Mouse Models and Inherited Disorders

Critical Role of Factor XIII in the Initial Stages of Carbon Tetrachloride–Induced Adult Liver Remodeling

MTA1 Coregulation of Transglutaminase 2 Expression and Function during Inflammatory Response

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