Novel transglutaminase inhibitors reverse the inflammation of allergic conjunctivitis

Sohn, Joon Hong; Kim, Tae Im; Yoon, Young Hee; Kim, Jooyong; Kim, Soo Youl

doi:10.1172/jci15937

Cited by 69 publications

(84 citation statements)

References 40 publications

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“…In this study, we provide evidence that TG2 could be an important factor in the mechanism through which sepsis develops, acting at multiple levels. Previous studies have shown that TG2 inhibitors can be useful in reversing some inflammatory processes (37). In the present study, we demonstrated that the ablation of TG2 confers resistance to LPS-induced septic shock in mice.…”

Section: Discussionsupporting

confidence: 70%

Transglutaminase Type II Is Involved in the Pathogenesis of Endotoxic Shock

Falasca

Farrace

Rinaldi

et al. 2008

The Journal of Immunology

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The pathogenesis of sepsis is characterized by the inability of the host to regulate the inflammatory response, and as a consequence, dysregulated inflammatory processes induce organ dysfunctions and death. Altered transglutaminase type II (TG2) expression is associated with the development of many inflammatory diseases. Therefore, in this study, we questioned whether TG2 could also contribute to the pathological inflammatory dysregulation occurring in septic shock in vivo. To this aim, we used as an experimental model the TG2 knockout mice, in which the process of septic shock was elicited by treatment with LPS. Interestingly, our results demonstrated that TG2 ablation leads to partial resistance to experimental sepsis. The increased survival of TG2−/− mice was reflected in a drastic reduction of organ injury, highlighted by a limited infiltration of neutrophils in kidney and peritoneum and by a better homeostasis of the proinflammatory mediators as well as mitochondrial function. We also showed that in wild-type mice, the TG2 expression is increased during endotoxemia and, being directly involved in the mechanisms of NF-κB activation, it may cause a continuous activation cycle in the inflammatory process, thus contributing to development of sepsis pathogenesis. We propose that the inhibition of TG2 could represent a novel approach in the treatment of inflammatory processes associated with sepsis.

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Section: Discussionsupporting

confidence: 70%

Transglutaminase Type II Is Involved in the Pathogenesis of Endotoxic Shock

Falasca

Farrace

Rinaldi

et al. 2008

The Journal of Immunology

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“…Mehta et al suggested that increased TGase 2 expression in MCF-7/DOX cells augmented the binding of integrins to extracellular matrix proteins (31). Increased expression of TGase 2 correlates with increased cell motility and adhesion (20,32,33), and cell adhesion induces activation of focal Table 3.…”

Section: Discussionmentioning

confidence: 99%

Reversal of Drug Resistance in Breast Cancer Cells by Transglutaminase 2 Inhibition and Nuclear Factor-κB Inactivation

et al. 2006

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Induction of transglutaminase 2 (TGase 2) by epidermal growth factor (EGF) in human breast cancer cells increases their oncogenic potential and chemoresistance. The role of TGase 2 in the development of these tumor-related phenotypes remains to be elucidated, but it has been shown that expression of a dominant-negative form of TGase 2 reverses EGF-mediated chemoresistance in breast cancer cells. We examined several different breast cancer cell lines, representing both EGF receptor (EGFR)-positive and EGFR-negative breast cancers, and found that doxorubicin-resistant cells had a higher level of TGase 2 compared with doxorubicin-sensitive cells independent of the EGFR expression level. TGase 2 inhibition increased the chemosensitivity of drug-resistant cells, concomitant with a decrease in nuclear factor-KB (NF-KB) activity. Increasing the level of TGase 2 in drugsensitive cells by transient transfection reduced the level of inhibitory subunit A of NF-KB (IKBA) and increased NF-KB activity in these cells. Inhibition of TGase 2 in drug-resistant cells by RNA interference increased the levels of IKBA, and this correlated with a shift in the accumulation of NF-KB from the nucleus to the cytosol. We recently showed that TGase 2 activated NF-KB through polymerization and depletion of free IKBA during inflammation. Therefore, increased expression of TGase 2 and subsequent activation of NF-KB may contribute to drug resistance in breast cancer cells independently of EGF signaling. (Cancer Res 2006; 66(22): 10936-43)

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“…Both modifications significantly augmented the activity of sPLA 2 . Peptide inhibitors of TG2 or peptides with dual inhibition of TG2 and PLA 2 significantly inhibited the inflammation associated with allergic conjunctivitis induced by ragweed in a guinea pig model (78) and lung inflammation induced by lipopolysaccharide (79). Both factor XIII and tissue TG have roles in regulating macrophage adhesion, migration and phagocytosis (50,74,80).…”

Section: Role Of Transglutaminases In Inflammationmentioning

confidence: 99%

Roles of transglutaminases in cardiac and vascular diseases

Sane

Kontos²,

Greenberg³

2007

Front Biosci

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All transglutaminases share the common enzymatic activity of transamidation, or the cross-linking of glutamine and lysine residues to form N epsilon (gamma-glutamyl) lysyl isopeptide bonds. The plasma proenzyme factor XIII is responsible for stabilizing the fibrin clot against physical and fibrinolytic disruption. Another member of the transglutaminase family, tissue transglutaminase or TG2 is abundantly expressed in cardiomyocytes, vascular cells and macrophages. The transglutaminases have a variety of functions independent of their transamidating activity. For example, TG2 binds and hydrolyzes GTP, thereby fostering signal transduction by several G protein coupled receptors. Accumulating evidence points to novel roles for factor XIII and TG2 in cardiovascular biology including: (a) modulating platelet activity, (b) regulating glucose control, (c) contributing to the development of hypertension, (d) influencing the progression of atherosclerosis, (e) regulating vascular permeability and angiogenesis (f) and contributing to myocardial signaling, contractile activity and ischemia/reperfusion injury. In this review, we summarize the cardiovascular biology of two members of the family of transglutaminases, Factor XIII and TG2.

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Novel transglutaminase inhibitors reverse the inflammation of allergic conjunctivitis

Cited by 69 publications

References 40 publications

Transglutaminase Type II Is Involved in the Pathogenesis of Endotoxic Shock

Transglutaminase Type II Is Involved in the Pathogenesis of Endotoxic Shock

Reversal of Drug Resistance in Breast Cancer Cells by Transglutaminase 2 Inhibition and Nuclear Factor-κB Inactivation

Roles of transglutaminases in cardiac and vascular diseases

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