Activator protein‐1 signalling pathway and apoptosis are modulated by poly(ADP‐ribose) polymerase‐1 in experimental colitis

Abstract

SUMMARYPoly(ADP-ribose) polymerase-1 (PARP-1) is activated in response to DNA injury in the nucleus of eukaryotic cells and has been implicated in intestinal barrier dysfunction during inflammatory bowel diseases. In this study we investigated whether PARP-1 may regulate the inflammatory response of experimental colitis at the level of signal transduction mechanisms. Mice genetically deficient of PARP-1 (PARP-1 -/-) and wild-type littermates were subjected to rectal instillation of trinitrobenzene sulphonic acid (TNBS). Signs of inflammation were monitored for 14 days. In wild-type mice, TNBS treatment resulted in colonic ulceration and marked apoptosis, which was associated with decreased colon content of the antiapoptotic protein Bcl-2, whereas the proapoptotic Bax was unchanged. Elevated levels of plasma nitrate/nitrite, metabolites of nitric oxide (NO), were also found. These inflammatory events were associated with activation of c-Jun-NH 2 terminal kinase (JNK), phosphorylation of c-Jun and activation of the nuclear transcription factor activator protein-1 (AP-1) in the colon. In contrast, PARP-1 -/-mice exhibited a significant reduction of colon damage and apoptosis, which was associated with increased colonic expression of Bcl-2 and lower levels of plasma nitrate/nitrite when compared to wild-type mice. Amelioration of colon damage was associated with a significant reduction of the activation of JNK and reduction of the DNA binding of AP-1. The data indicate that PARP-1 exerts a pathological role in colitis possibly by regulating the early stress-related transcriptional response through a positive modulation of the AP-1 and JNK pathways.

Protective effect of ellagic acid, a natural polyphenolic compound, in a murine model of Crohn's disease

“…In further support of a direct role for JNK in intestinal pathophysiology, PARP-1 -/-mice were noted to have less severe TNBS-induced colitis in association with reduced JNK and AP-1 DNA binding activity [35]. Besides, previous data from our research group found that the expression and activity of p38 and JNK were increased in rats with TNBS-induced colitis.…”

Role of poly(ADP‐ribose) polymerases in the regulation of inflammatory processes

“…The first one identified was NFjB [16] providing an explanation at the molecular level for the protection of PARP-1 knockout mice from endotoxin shock. Several other transcription factors and cofactors involved in inflammatory regulation such as NFAT [17,18], AP-1 [19][20][21][22], YY1 [23], sp1 [24], SIRT1 [25,26] were also found to be modulated by PARP-1. Recent data pointed towards the involvement of other PARP enzymes in the transcriptional regulation of inflammatory processes.…”

Transcriptional Reprogramming and Resistance to Colonic Mucosal Injury in Poly(ADP-ribose) Polymerase 1 (PARP1)-deficient Mice

“…PARP1 potentiates NF-B activity and AP-1 expression, fostering the expression of major NF-B and AP-1-depandant proinflammatory mediators (12). In intestinal epithelial cells in vitro, inhibition of PARP-1 with PJ-34 is protective during invasive Salmonella spp.…”

“…Genetic ablation or pharmacological inhibition of PARP1 reduces the biological and physical manifestations of experimental colitis; Il-10 Ϫ/Ϫ mice treated with a PARP1 inhibitor (3-aminobenzamide) show a significant reduction in proinflammatory cytokine production associated with reduced intestinal permeability (6). Other PARP1 inhibitors have also been used successfully to prevent hapten-induced colitis in rats (7)(8)(9)(10)(11) and in mice (12,13). However, the mechanism(s) underlying PARP-mediated promotion of immune dysregulation in colitis remains unknown, although depletion of cellular energetic pools, which could culminate in cell dysfunction and necrosis as well as the promotion of the transcription of proinflammatory genes, has been postulated (2).…”