Transglutaminases in Crohn's disease.

D’Argenio, Giuseppe; Biancone, Livia; Cosenza, V.; Valle, Nicola Della; D’Armiento, Francesco Paolo; Boirivant, Monica; Pallone, F.; Mazzacca, G

doi:10.1136/gut.37.5.690

Cited by 44 publications

(29 citation statements)

References 31 publications

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“…TG2 is a demidating/transamidating pleiotropic enzyme, deeply involved in inflammatory processes 32 and central in the pathogenesis of several diseases such as celiac disease and IBD. 33,34 CysN inhibits TG2 by different mechanisms; in fact, it is a diamine acting not only as a amine substrate competing with natural, endogenous substrates (competitive inhibition) but also as an irreversible inhibitor. This latter effect could be linked to the formation of stable complexes between TG2 active site and CysN or by the oxidation of the disulfide bond in the TG2.…”

Section: Cystamine Reduces Inflammation L Elli Et Almentioning

confidence: 99%

Beneficial effects of treatment with transglutaminase inhibitor cystamine on the severity of inflammation in a rat model of inflammatory bowel disease

Elli

Ciulla

Busca

et al. 2011

Laboratory Investigation

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Inflammatory bowel disease (IBD) represents a socially and clinically relevant disorder, characterized by intestinal chronic inflammation. Cystamine (CysN) is a multipotent molecule with healthy effects and, moreover, it is an inhibitor of transglutaminases (TGs), including the TG type 2 (TG2), an enzyme with pleiotropic functions, involved in different pathways of inflammation and central in the pathogenesis of some human disorders as the IBD. Our aim was to evaluate the effect of CysN in an IBD rat model. A total of 30 rats were divided into 4 groups: controls without treatment (CTR; n ¼ 7); receiving the 2,4,6-trinitrobenzene sulfonic acid enema (TNBS group; n ¼ 8); treated with TNBS enema plus oral CysN (TNBS-CysN group; n ¼ 8); treated with CysN (CysN group; n ¼ 7). After killing, bowel inflammation was evaluated applying specific scores. TG activity, TG2 and isopeptide bond immunohistochemical expression, and tumor necrosis factor-a (TNF-a) were evaluated in the colonic tissue, such as interleukin-6 (IL-6) serological levels (ELISA). TG2 was also evaluated on the luminal side of the colon by immunoautoradiography. Colonic samples from IBD patients were compared with animal results. TNBS-CysN group developed a less severe colitis compared with the TNBS group (macroscopic score 0.43 ± 0.78 vs 3.28 ± 0.95, microscopic score 6.62 ± 12.01 vs 19.25 ± 6.04, Po0.05, respectively) associated with a decrease of TG activity, TG2 and isopeptide bond immunohistochemical expression, TNF-a and IL-6 levels. No statistically significant differences were found between CysN and CTR groups. The colonic immunolocalization of TG2 was comparable in humans affected by IBD and TNBS-administered animals. This is the first demonstration that treatment with a CysN has an anti-inflammatory effect, reducing severity of colitis in a rat model. CysN could be tested as a possible treatment or co-treatment in IBD therapeutic trials.

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Section: Cystamine Reduces Inflammation L Elli Et Almentioning

confidence: 99%

Beneficial effects of treatment with transglutaminase inhibitor cystamine on the severity of inflammation in a rat model of inflammatory bowel disease

Elli

Ciulla

Busca

et al. 2011

Laboratory Investigation

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“…On the other hand, increased tTG has been demonstrated in the intestines of patients with CD and Crohn disease (6,20 ). This antigenic overexpression could explain, at least in part, the anti-tTG induction observed in these patients.…”

Section: Anti-tissue Transglutaminase Antibodies In Arthriticmentioning

confidence: 95%

Anti-Tissue Transglutaminase Antibodies in Arthritic Patients: A Disease-specific Finding?

Picarelli¹,

Tola²,

Sabbatella³

et al. 2003

Clinical Chemistry

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with 50 g/L OLZ added. As can be seen in Fig. 1D, extracts from protein precipitation and solid-phase methods showed a substantial reduction in instrument response compared with mobile phase. In contrast, the ethyl acetate liquid-liquid preparation used in our assay suppressed the signal of the analytes by Ͻ3%.This assay, because of the high simplicity of the extraction procedure, the short duration of the analysis, the small amount of starting sample needed, and its high selectivity, is being used routinely by our research group to monitor plasma OLZ concentrations in schizophrenic patients. In fact, in a set of 17 smoking and nonsmoking patients, a wide drug concentration range was found [0.8 -71 g/L; mean (SD), 34 (4) g/L for doses between 5 and 10 mg/24 h], consistent with the large variability of OLZ pharmacokinetics reported previously (16 ).The high sensitivity shown by this assay makes it suitable for measuring the extremely low concentrations of OLZ in schizophrenic patients who are heavy smokers. It could also potentially be helpful in clarifying the clinically relevant role played by smoking, through increases in the clearance of OLZ via CYP1A2, and in demonstrating the marked variability of the antipsychotic response in schizophrenic patients (2 ). Likewise, the method could potentially be very useful for monitoring those patients who are given other drugs capable of inducing OLZ metabolism (e.g., anticonvulsants and barbiturates).

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“…These diseases include celiac disease (17), Crohn disease (18), and sporadic inclusion-body myositis (19). An increase of TGase 2 activity in these diseases might be associated with important physiological regulation such as activation of PLA 2 .…”

Section: Discussionmentioning

confidence: 99%

“…Several physiological roles for TGase 2 have been demonstrated, such as wound healing (13), fibrosis (14), apoptosis (15), and matrix formation (16). Increased TGase 2 expression has been reported to occur in many inflammatory diseases, such as celiac disease (17), Crohn disease (18), and sporadic inclusion-body myositis (19). Pathological roles of TGase 2 in those diseases might be associated with activation of PLA 2 .…”

Section: Introductionmentioning

confidence: 99%

Novel transglutaminase inhibitors reverse the inflammation of allergic conjunctivitis

Sohn¹,

Kim²,

Yoon³

et al. 2003

J. Clin. Invest.

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2 ), including uteroglobin and lipocortin-1 (annexin I). Uteroglobin and lipocortin-1 retain several conserved sequences. Based on these sequences, several nonapeptides (antiflammins) were synthesized. These nonapeptides were shown to have anti-inflammatory effects in vitro and in vivo, possibly by inhibiting PLA 2 . Subsequent research showed that PLA 2 is activated by transglutaminase 2 (TGase 2). We hypothesize here that TGase 2 inhibitors may increase the anti-inflammatory efficacy of inhibiting PLA 2 activity. To test this theory, we constructed recombinant peptides containing sequences from pro-elafin (for inhibition of TGase 2), and from lipocortin-1, lipocortin-5, and uteroglobin (for inhibition of PLA 2 ). The recombinant peptides, which had dual inhibitory effects on purified TGase 2 and PLA 2 , reversed the inflammation of allergic conjunctivitis to ragweed in a guinea pig model. The present work suggests that novel recombinant peptides may be safe and effective agents for the treatment of various inflammatory diseases.

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Transglutaminases in Crohn's disease.

Abstract: Transglutaminases are a family of Cadependent enzymes involved in various biological events. Circulating transglutaminase (factor XIIIa) is decreased in blood of patients with inflammatory bowel diseases.

Cited by 44 publications

References 31 publications

Beneficial effects of treatment with transglutaminase inhibitor cystamine on the severity of inflammation in a rat model of inflammatory bowel disease

Beneficial effects of treatment with transglutaminase inhibitor cystamine on the severity of inflammation in a rat model of inflammatory bowel disease

Anti-Tissue Transglutaminase Antibodies in Arthritic Patients: A Disease-specific Finding?

Novel transglutaminase inhibitors reverse the inflammation of allergic conjunctivitis

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