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Vitamin D/VDR signaling pathway ameliorates 2,4,6-trinitrobenzene sulfonic acid-induced colitis by inhibiting intestinal epithelial apoptosis.

Zhu T, Liu TJ, Shi YY, Zhao Q - Int. J. Mol. Med. (2015)

Bottom Line: The excessive apoptosis of intestinal epithelial cells (IECs) partly accounts for the development of colonic inflammation and eventually results in IBD.PUMA expression showed the same tendency; however, the p53 protein level was not altered.The mechanisms involved include the downregulation of PUMA expression.

View Article: PubMed Central - PubMed

Affiliation: Department of Pediatric Orthopedics, Shengjing Hospital of China Medical University, Shenyang, Liaoning 110004, P.R. China.

ABSTRACT
Increasing epidemiological data have suggested a link between vitamin D deficiency and the incidence of inflammatory bowel disease (IBD). In the present study, we confirmed that vitamin D deficiency, as well as the decreased local expression of vitamin D receptor (VDR), was prevalent in an IBD cohort. The excessive apoptosis of intestinal epithelial cells (IECs) partly accounts for the development of colonic inflammation and eventually results in IBD. Based on the established inhibitory effects of the vitamin D/VDR pathway on IEC apoptosis, we treated mice with 2,4,6-trinitrobenzene sulfonic acid (TNBS)-induced colitis with paricalcitol, a vitamin D analog, in order to investigate the mechanisms responsible for the inhibitory effects of the vitamin D/VDR pathway. We observed that following treatment with vitamin D, the mice presented with only minor bodyweight loss, and the mice also showed improved histological scores and decreased intestinal epithelial permeability compared with the vehicle-treated group. The colonic mRNA expression of inflammatory cytokines and chemokines was markedly suppressed, indicating less severe colitis in the vitamin D-treated mice. Subsequently, we investigated p53 upregulated modulator of apoptosis (PUMA) and p53, two major independent pathways of apoptosis, as well as caspase-3. We found that the vitamin D-treated mice had lower expression levels of caspase-3 than the vehicle-treated mice. PUMA expression showed the same tendency; however, the p53 protein level was not altered. The present study indicates that vitamin D attenuates the development of TNBS-induced colitis by inhibiting the apoptosis of IECs. The mechanisms involved include the downregulation of PUMA expression. Our data provide experimental support for the clinical trials of vitamin D intervention in patients with IBD.

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The vitamin D analog, paricalcitol, ameliorates TNBS-induced colitis. (A) Body weight changes over time in the vehicle-treated group and vitamin D-treated group after the TNBS injection. **P<0.01, ***P<0.001 vs. vehicle treatment (n=8 in each group). (B) Colon morphology. (C) Macroscopic scoring of colon morphology. (D) H&E staining of distal colon. (E) Microscopic scoring of H&E-stained slides (original magnification, x100) from the vehicle- and paricalcitol-treated groups on day 4 after the TNBS injection or from the control group (50% ethanol injection). TNBS, 2,4,6-trinitrobenzene sulfonic acid.
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f2-ijmm-35-05-1213: The vitamin D analog, paricalcitol, ameliorates TNBS-induced colitis. (A) Body weight changes over time in the vehicle-treated group and vitamin D-treated group after the TNBS injection. **P<0.01, ***P<0.001 vs. vehicle treatment (n=8 in each group). (B) Colon morphology. (C) Macroscopic scoring of colon morphology. (D) H&E staining of distal colon. (E) Microscopic scoring of H&E-stained slides (original magnification, x100) from the vehicle- and paricalcitol-treated groups on day 4 after the TNBS injection or from the control group (50% ethanol injection). TNBS, 2,4,6-trinitrobenzene sulfonic acid.

Mentions: We used a mouse model of TNBS-induced colitis to mimic the pathological process of IBD. Paricalcitol, a vitamin D analog, was administrated to investigate the protective role of the vitamin D/VDR signaling pathway. Paricalcitol has been proven to exert the same curative effect as calcitriol, but it produces less side-effects, including less hypercalcemia (19,20). After the TNBS injection, the body weight of the mice in both the vitamin D-treated group (VD) and the vehicle-treated group (VE) decreased over time, but the mice in the VD group only developed mild colitis with minor weight loss (Fig. 2A). In the gross observation, the colons of the mice in the VD group were much closer to normal than those of the mice in the VE group (Fig. 2B). Microscopic examination revealed severe hemorrhage, inflammatory cell infiltration and the breakdown of the normal intestinal tissue barrier in the mice in the VE group, while the mice in the VD group presented minimal histological damage (Fig. 2D). The mice in the VE group also had a higher macroscopic score (Fig. 2C) and histological score (Fig. 2E) than the mice in the VD group. These results provide evidence that TNBS-induced colitis may be substantially suppressed by the administration of vitamin D.


Vitamin D/VDR signaling pathway ameliorates 2,4,6-trinitrobenzene sulfonic acid-induced colitis by inhibiting intestinal epithelial apoptosis.

Zhu T, Liu TJ, Shi YY, Zhao Q - Int. J. Mol. Med. (2015)

The vitamin D analog, paricalcitol, ameliorates TNBS-induced colitis. (A) Body weight changes over time in the vehicle-treated group and vitamin D-treated group after the TNBS injection. **P<0.01, ***P<0.001 vs. vehicle treatment (n=8 in each group). (B) Colon morphology. (C) Macroscopic scoring of colon morphology. (D) H&E staining of distal colon. (E) Microscopic scoring of H&E-stained slides (original magnification, x100) from the vehicle- and paricalcitol-treated groups on day 4 after the TNBS injection or from the control group (50% ethanol injection). TNBS, 2,4,6-trinitrobenzene sulfonic acid.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4380119&req=5

f2-ijmm-35-05-1213: The vitamin D analog, paricalcitol, ameliorates TNBS-induced colitis. (A) Body weight changes over time in the vehicle-treated group and vitamin D-treated group after the TNBS injection. **P<0.01, ***P<0.001 vs. vehicle treatment (n=8 in each group). (B) Colon morphology. (C) Macroscopic scoring of colon morphology. (D) H&E staining of distal colon. (E) Microscopic scoring of H&E-stained slides (original magnification, x100) from the vehicle- and paricalcitol-treated groups on day 4 after the TNBS injection or from the control group (50% ethanol injection). TNBS, 2,4,6-trinitrobenzene sulfonic acid.
Mentions: We used a mouse model of TNBS-induced colitis to mimic the pathological process of IBD. Paricalcitol, a vitamin D analog, was administrated to investigate the protective role of the vitamin D/VDR signaling pathway. Paricalcitol has been proven to exert the same curative effect as calcitriol, but it produces less side-effects, including less hypercalcemia (19,20). After the TNBS injection, the body weight of the mice in both the vitamin D-treated group (VD) and the vehicle-treated group (VE) decreased over time, but the mice in the VD group only developed mild colitis with minor weight loss (Fig. 2A). In the gross observation, the colons of the mice in the VD group were much closer to normal than those of the mice in the VE group (Fig. 2B). Microscopic examination revealed severe hemorrhage, inflammatory cell infiltration and the breakdown of the normal intestinal tissue barrier in the mice in the VE group, while the mice in the VD group presented minimal histological damage (Fig. 2D). The mice in the VE group also had a higher macroscopic score (Fig. 2C) and histological score (Fig. 2E) than the mice in the VD group. These results provide evidence that TNBS-induced colitis may be substantially suppressed by the administration of vitamin D.

Bottom Line: The excessive apoptosis of intestinal epithelial cells (IECs) partly accounts for the development of colonic inflammation and eventually results in IBD.PUMA expression showed the same tendency; however, the p53 protein level was not altered.The mechanisms involved include the downregulation of PUMA expression.

View Article: PubMed Central - PubMed

Affiliation: Department of Pediatric Orthopedics, Shengjing Hospital of China Medical University, Shenyang, Liaoning 110004, P.R. China.

ABSTRACT
Increasing epidemiological data have suggested a link between vitamin D deficiency and the incidence of inflammatory bowel disease (IBD). In the present study, we confirmed that vitamin D deficiency, as well as the decreased local expression of vitamin D receptor (VDR), was prevalent in an IBD cohort. The excessive apoptosis of intestinal epithelial cells (IECs) partly accounts for the development of colonic inflammation and eventually results in IBD. Based on the established inhibitory effects of the vitamin D/VDR pathway on IEC apoptosis, we treated mice with 2,4,6-trinitrobenzene sulfonic acid (TNBS)-induced colitis with paricalcitol, a vitamin D analog, in order to investigate the mechanisms responsible for the inhibitory effects of the vitamin D/VDR pathway. We observed that following treatment with vitamin D, the mice presented with only minor bodyweight loss, and the mice also showed improved histological scores and decreased intestinal epithelial permeability compared with the vehicle-treated group. The colonic mRNA expression of inflammatory cytokines and chemokines was markedly suppressed, indicating less severe colitis in the vitamin D-treated mice. Subsequently, we investigated p53 upregulated modulator of apoptosis (PUMA) and p53, two major independent pathways of apoptosis, as well as caspase-3. We found that the vitamin D-treated mice had lower expression levels of caspase-3 than the vehicle-treated mice. PUMA expression showed the same tendency; however, the p53 protein level was not altered. The present study indicates that vitamin D attenuates the development of TNBS-induced colitis by inhibiting the apoptosis of IECs. The mechanisms involved include the downregulation of PUMA expression. Our data provide experimental support for the clinical trials of vitamin D intervention in patients with IBD.

Show MeSH
Related in: MedlinePlus