» Articles » PMID: 22749932

Increased Levels of Survivin, Via Association with Heat Shock Protein 90, in Mucosal T Cells from Patients with Crohn's Disease

Overview
Specialty Gastroenterology
Date 2012 Jul 4
PMID 22749932
Citations 14
Authors
Affiliations
Soon will be listed here.
Abstract

Background & Aims: Defective apoptosis of lamina propria T cells (LPTs) is involved in the pathogenesis of Crohn's disease. Survivin, a member of the inhibitors of apoptosis family, prevents cell death and regulates cell division. Survivin has been studied extensively in cancer, but little is known about its role in Crohn's disease.

Methods: LPTs were isolated from mucosal samples of patients with Crohn's disease or ulcerative colitis and healthy individuals (controls). LPTs were activated with interleukin-2 or via CD3, CD2, and CD28 signaling, and cultured at 42°C to induce heat shock. Survivin expression was assessed by immunohistochemistry, confocal microscopy, and immunoblotting; survivin levels were reduced by RNA interference. Cell viability, apoptosis, and proliferation were measured by trypan blue exclusion, annexin-V/7-Aminoactinomycin D staining, and uptake of [3]thymidine, respectively.

Results: LPTs from patients with Crohn's disease had higher levels of survivin than LPTs from patients with ulcerative colitis or controls. RNA knockdown of survivin in LPTs inhibited their proliferation and promoted apoptosis. Levels of survivin were low in LPTs from patients with ulcerative colitis and controls as a result of ubiquitin-mediated proteasome degradation. In LPTs from patients with Crohn's disease, survivin bound to the heat shock protein (HSP)90, and therefore was resistant to proteasome degradation. Incubating LPTs with 17-N-allylamino-17-demethoxygeldanamycin, an inhibitor of HSP90, reduced levels of survivin and induced apoptosis.

Conclusions: Levels of survivin are increased in LPTs from patients with Crohn's disease (compared with ulcerative colitis and controls) because survivin interacts with HSP90 and prevents proteasome degradation. This allows LPTs to avoid apoptosis. Strategies to restore apoptosis to these cells might be developed to treat patients with Crohn's disease.

Citing Articles

Dysregulation of Survivin-Targeting microRNAs in Autoimmune Diseases: New Perspectives for Novel Therapies.

Shomali N, Maashi M, Baradaran B, Daei Sorkhabi A, Sarkesh A, Mohammadi H Front Immunol. 2022; 13:839945.

PMID: 35309327 PMC: 8927965. DOI: 10.3389/fimmu.2022.839945.


Emerging Pathological Engagement of Ferroptosis in Gut Diseases.

Gao W, Zhang T, Wu H Oxid Med Cell Longev. 2021; 2021:4246255.

PMID: 34733403 PMC: 8560274. DOI: 10.1155/2021/4246255.


Ablation of Survivin in T Cells Attenuates Acute Allograft Rejection after Murine Heterotopic Heart Transplantation by Inducing Apoptosis.

Xu H, Yu J, Cui J, Chen Z, Zhang X, Zou Y Front Immunol. 2021; 12:710904.

PMID: 34421916 PMC: 8377163. DOI: 10.3389/fimmu.2021.710904.


Gatekeepers of the Gut: The Roles of Proteasomes at the Gastrointestinal Barrier.

Mohapatra G, Eisenberg-Lerner A, Merbl Y Biomolecules. 2021; 11(7).

PMID: 34356615 PMC: 8301830. DOI: 10.3390/biom11070989.


Survivin Promotes Piperlongumine Resistance in Ovarian Cancer.

Nan X, Gong L, Chen X, Zhou H, Ye P, Yang Y Front Oncol. 2019; 9:1345.

PMID: 31850227 PMC: 6895030. DOI: 10.3389/fonc.2019.01345.


References
1.
Ambrosini G, Adida C, Sirugo G, Altieri D . Induction of apoptosis and inhibition of cell proliferation by survivin gene targeting. J Biol Chem. 1998; 273(18):11177-82. DOI: 10.1074/jbc.273.18.11177. View

2.
Knauer S, Bier C, Habtemichael N, Stauber R . The Survivin-Crm1 interaction is essential for chromosomal passenger complex localization and function. EMBO Rep. 2006; 7(12):1259-65. PMC: 1794705. DOI: 10.1038/sj.embor.7400824. View

3.
Li F, Ambrosini G, Chu E, Plescia J, Tognin S, Marchisio P . Control of apoptosis and mitotic spindle checkpoint by survivin. Nature. 1998; 396(6711):580-4. DOI: 10.1038/25141. View

4.
Workman P . Overview: translating Hsp90 biology into Hsp90 drugs. Curr Cancer Drug Targets. 2003; 3(5):297-300. DOI: 10.2174/1568009033481868. View

5.
Peer D, Park E, Morishita Y, Carman C, Shimaoka M . Systemic leukocyte-directed siRNA delivery revealing cyclin D1 as an anti-inflammatory target. Science. 2008; 319(5863):627-30. PMC: 2490797. DOI: 10.1126/science.1149859. View