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Cell Survival Failure in Effector T Cells From Patients With Systemic Lupus Erythematosus Following Insufficient Up-Regulation of Cold-Shock Y-Box Binding Protein 1.
- Source :
-
Arthritis & rheumatology (Hoboken, N.J.) [Arthritis Rheumatol] 2020 Oct; Vol. 72 (10), pp. 1721-1733. Date of Electronic Publication: 2020 Aug 26. - Publication Year :
- 2020
-
Abstract
- Objective: The importance of cold-shock Y-box binding protein 1 (YB-1) for cell homeostasis is well-documented based on prior observations of its association with certain cancer entities. This study was undertaken to explore the role of YB-1 in T cell homeostasis and survival and the potential contribution of YB-1 to the pathogenesis of systemic lupus erythematosus (SLE).<br />Methods: In the peripheral blood from 25 SLE patients and 25 healthy donors, the expression of YB-1 and frequency of T cell apoptosis was analyzed by quantitative polymerase chain reaction (qPCR) and fluorescence-activated cell sorting of CD4+ T cells ex vivo and also analyzed in T cells in vitro after 6 days of stimulation with anti-CD3-coupled or anti-CD3/anti-CD28-coupled microspheres. YB-1 was overexpressed using lentiviral transduction with wild-type green fluorescent protein (wtGFP) YB-1, and knockdown of YB-1 was achieved using specific short hairpin RNA (shRNA) (3-fold reduction; P < 0.0001).<br />Results: YB-1 expression was significantly lower in apoptosis-prone T cells and in activated T cells from SLE patients compared to YB-1 expression in nonapoptotic T cells and activated T cells from healthy donors (P = 0.001). Knockdown of YB-1 in T cells consequently led to expression of proapoptotic molecules and caspase 3 activation (1.6-fold), and subsequently, to apoptosis. Furthermore, YB-1 promoted survival pathways involving enhanced protein expression of the kinase Akt (2-fold) and Bcl-2 (3-fold), even when Fas/CD95 was triggered. YB-1-mediated T cell survival was reversed by Akt and phosphatidylinositol 3-kinase (PI3K) inactivation. In SLE patients, rescue of YB-1 expression strongly promoted survival of T cells and even prevented cell death in T cells that were extremely apoptosis-prone.<br />Conclusion: Our data show that failure of YB-1 up-regulation in T cells from SLE patients led to enhanced apoptosis. These findings imply that YB-1 plays a crucial role in the disturbed homeostasis of activated T cells leading to hematopoietic alterations in SLE. These insights may help facilitate the development of new treatment strategies for SLE.<br /> (© 2020 The Authors. Arthritis & Rheumatology published by Wiley Periodicals LLC on behalf of American College of Rheumatology.)
- Subjects :
- Adult
Aged
Apoptosis physiology
Female
Humans
Leukocytes, Mononuclear metabolism
Lupus Erythematosus, Systemic genetics
Male
Middle Aged
Up-Regulation
Y-Box-Binding Protein 1 genetics
Young Adult
Cell Survival physiology
Lupus Erythematosus, Systemic metabolism
Signal Transduction physiology
T-Lymphocytes metabolism
Y-Box-Binding Protein 1 metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 2326-5205
- Volume :
- 72
- Issue :
- 10
- Database :
- MEDLINE
- Journal :
- Arthritis & rheumatology (Hoboken, N.J.)
- Publication Type :
- Academic Journal
- Accession number :
- 32475063
- Full Text :
- https://doi.org/10.1002/art.41382