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

Abstract

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.

Transglutaminase factor XIII promotes arthritis through mechanisms linked to inflammation and bone erosion

“…For instance, using 2,4,6-trinitrobenzenesulfonic acid-induced colitis as a model of inflammatory bowel disease in rats, it was demonstrated that cystamine treatment markedly diminished colitis-associated inflammation including reduced mucosal proinflammatory cytokine expression. 60 Likewise, cysteamine-mediated inhibition of transglutaminase activity was shown to limit the severity and progression of experimental autoimmune encephalomyelitis, a model of multiple sclerosis in mice. 61 Thus, inhibiting transglutaminase function may be beneficial in limiting a wide array of inflammatory diseases.…”

Increased tissue transglutaminase activity contributes to central vascular stiffness in eNOS knockout mice

“…Cystamine is a TG inhibitor that has been widely used in animal models to study the role of TG (2,7,9,10). In the present study, to examine the role of TG2 in mediating vascular properties, cystamine (40 mg·kg Ϫ1 ·day Ϫ1 ) was delivered to WT and eNOS Ϫ/Ϫ mice for 4 wk using osmotic infusion pumps.…”

Transglutaminase is a Critical Link Between Inflammation and Hypertension

“…Transglutaminases (TGases) are a widely distributed family of enzymes that modify proteins through the hydrolytic deamination or transamidation of the carboxamide moiety of glutamine residues on proteins . Several lines of evidence link TGases with inflammation and hypertension . Initial evidence that TGase contributes to hypertension came from studies showing that cystamine, a transglutaminase inhibitor, reduced blood pressure in the spontaneously hypertensive rat .…”

“…15 Several lines of evidence link TGases with inflammation and hypertension. [16][17][18][19][20][21] Initial evidence that TGase contributes to hypertension came from studies showing that cystamine, a transglutaminase inhibitor, reduced blood pressure in the spontaneously hypertensive rat. 22 More recently, we showed that circulating TGase activity is significantly elevated in women with preeclampsia and in an experimental model of preeclampsia in mice.…”