PUMA-mediated intestinal epithelial apoptosis contributes to ulcerative colitis in humans and mice

Qiu, Wei; Wu, Bin; Wang, Xinwei; Buchanan, Monica E.; Regueiro, Miguel; Hartman, Douglas J.; Schoen, Robert E.; Yu, Jian; Zhang, Lin

doi:10.1172/jci42917

Cited by 167 publications

(184 citation statements)

References 38 publications

Supporting

Mentioning

164

Contrasting

Unclassified

Order By: Relevance

“…Intracellular (cytoplasmic and nuclear) PARP1 is known for protection against genomic instability but also controls several forms of cell death, the effect attributed to energetic failure due to NAD ϩ depletion (29), activation of mitochondrial apoptosis inducible factor via its PAR-binding domain (30), or through activation of redoxsensitive cation channel TRPM2 (31) among other mechanisms. Therefore, the protection we observed in Parp1 Ϫ/Ϫ mice from DSS-mediated colitis, a model reliant on a direct toxic and pro-apoptotic effect on colonic epithelial cells (32), could be attributed to the resistance of the colonocytes to DSS-related cytotoxicity. However, the observed lack of protection in B-and T-cell-deficient Parp1 Ϫ/Ϫ mice (Rag2…”

Section: Discussionmentioning

confidence: 88%

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

Larmonier

Shehab

Laubitz

et al. 2016

Journal of Biological Chemistry

View full text Add to dashboard Cite

Poly(ADP-ribose) polymerases (PARPs) synthesize and bind branched polymers of ADP-ribose to acceptor proteins using NAD as a substrate and participate in the control of gene transcription and DNA repair. PARP1, the most abundant isoform, regulates the expression of proinflammatory mediator cytokines, chemokines, and adhesion molecules, and inhibition of PARP1 enzymatic activity reduced or ameliorated autoimmune diseases in several experimental models, including colitis. However, the mechanism(s) underlying the protective effects of PARP1 inhibition in colitis and the cell types in which Parp1 deletion has the most significant impact are unknown. The objective of the current study was to determine the impact of Parp1 deletion on the innate immune response to mucosal injury and on the gut microbiome composition. were protected from dextran-sulfate sodium-induced colitis and that this protection was associated with a dramatic transcriptional reprogramming in the colon. PARP1 deficiency was also associated with a modulation of the colonic microbiota (increases relative abundance of Clostridia clusters IV and XIVa) and a concomitant increase in the frequency of mucosal CD4 ؉ CD25 ؉ Foxp3 ؉ regulatory T cells. The protective effects conferred by Parp1 deletion were lost in Rag2

show abstract

Section: Discussionmentioning

confidence: 88%

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

Larmonier

Shehab

Laubitz

et al. 2016

Journal of Biological Chemistry

View full text Add to dashboard Cite

show abstract

“…In HCT116 cells, a human colonic cancer cell line, TNF-α markedly induced PUMA, and the induction was attenuated by 1,25(OH) 2 D 3 ( Figure 9A). PUMA is regulated by NF-κB, and a functional cis-κB site has been identified in the PUMA gene promoter (12,14) (Figure 9B). ChIP assays showed that 1,25(OH) 2 D 3 blocked TNF-α-induced p65 binding to this κB site in HCT116 cells ( Figure 9C), and EMSA confirmed that 1,25(OH) 2 D 3 attenuated TNF-α-induced NF-κB binding to the PUMA κB probe in HCT116 nuclear extracts ( Figure 9D).…”

Section: Reconstitution Of Vdr-null Epithelial Cells With Hvdr Rescuementioning

confidence: 99%

“…Indeed, TNF-α and IFN-γ, two cytokines critical to IBD pathogenesis, induce IEC apoptosis (11). Recent studies demonstrated that p53-upregulated modulator of apoptosis (PUMA) is a key mediator of IEC apoptosis in IBD (12). PUMA is a BH3 domain proapoptotic BCL2 family member that interacts with antiapoptotic BCL2 family members to activate proapoptotic BAX and BAK and trigger mitochondrial dysfunction.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Intestinal epithelial vitamin D receptor signaling inhibits experimental colitis

et al. 2013

View full text Add to dashboard Cite

The inhibitory effects of vitamin D on colitis have been previously documented. Global vitamin D receptor (VDR) deletion exaggerates colitis, but the relative anticolitic contribution of epithelial and nonepithelial VDR signaling is unknown. Here, we showed that colonic epithelial VDR expression was substantially reduced in patients with Crohn's disease or ulcerative colitis. Moreover, targeted expression of human VDR (hVDR) in intestinal epithelial cells (IECs) protected mice from developing colitis. In experimental colitis models induced by 2,4,6-trinitrobenzenesulfonic acid, dextran sulfate sodium, or CD4 + CD45RB hi T cell transfer, transgenic mice expressing hVDR in IECs were highly resistant to colitis, as manifested by marked reductions in clinical colitis scores, colonic histological damage, and colonic inflammation compared with WT mice. Reconstitution of Vdr-deficient IECs with the hVDR transgene completely rescued Vdr-null mice from severe colitis and death, even though the mice still maintained a hyperresponsive Vdr-deficient immune system. Mechanistically, VDR signaling attenuated PUMA induction in IECs by blocking NF-κB activation, leading to a reduction in IEC apoptosis. Together, these results demonstrate that gut epithelial VDR signaling inhibits colitis by protecting the mucosal epithelial barrier, and this anticolitic activity is independent of nonepithelial immune VDR actions.

show abstract

“…Caspase-3, a key enzyme in apoptosis, is activated in apoptotic cells through both extrinsic and intrinsic pathway. This causes colonic destruction with disturbed functions (Qiu et al, 2011).…”

Section: Introductionmentioning

confidence: 99%

Evaluation of the colo-protective effects of tadalafil in an experimental model of ulcerative colitis in rats

Labib¹,

Abdelzaher²,

Shaker³

et al. 2017

Afr. J. Pharm. Pharmacol.

View full text Add to dashboard Cite

Ulcerative colitis is a serious premalignant condition with a confusing multifactorial pathogenesis. It should warrant all attention by researchers, for exploration of new prophylactic or therapeutic drugs targeting its pathophysiology. The current study was conducted to study the possible role of tadalafil and its potential actions in ulcerative colitis rat model, induced by acetic acid. Forty eight male Wistar albino rats were classified into 6 groups: control group, acetic acid (AA)-ulcerated group, AA-ulcerated + tadalafil (1 mg/kg/day), AA-ulcerated + tadalafil (5 mg/kg/day), AA-ulcerated + tadalafil (10 mg/kg/day) and AA-ulcerated + sulfasalazine 100 mg/kg/day groups. Tissue malondialdehyde (MDA), superoxide dismutase (SOD) and myeloperoxidase (MPO) were determined. Also, caspase-3 gene expression was measured as an indicator of apoptosis. Histopathological examination of the colonic tissue was also done. In addition, serum levels of interleukin (IL)-1β and tumour necrosis factor (TNF)-α were measured. In AA-ulcerated group, there was significant elevation in tissue MDA levels and MPO activity with upregulation of caspase 3 gene expression. Meanwhile, AA caused decreases in the SOD activities. Also, AA induced elevation in the serum IL-1β and TNF-α levels. Pretreatment with tadalafil in doses of 1, 5 and 10 mg/kg/days guarded against changes in these parameters. Its effects were dose-dependent. According to the results, pretreatment with tadalafil in doses of 1, 5 and 10 mg/kg/day exerted dosedependent beneficial effects against AA-induced damage of the colon, possibly by exerting antiinflammatory and antioxidant effects. Also, reduction of apoptosis proved to be one of the contributing protective mechanisms of actions.

show abstract

PUMA-mediated intestinal epithelial apoptosis contributes to ulcerative colitis in humans and mice

Cited by 167 publications

References 38 publications

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

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

Intestinal epithelial vitamin D receptor signaling inhibits experimental colitis

Evaluation of the colo-protective effects of tadalafil in an experimental model of ulcerative colitis in rats

Contact Info

Product

Resources

About