Abstract: FR-PO226

GLCCI1 as a Novel Therapeutic Target of Glucocorticoid-Resistant T-Cells

Session Information

Category: Cell Biology

  • 202 Apoptosis, Proliferation, Autophagy, Cell Senescence, Cell Transformation

Authors

  • Nishibori, Yukino, Kyorin University School of Medicine, Tokyo, Japan
  • Kiuchi, Zentaro, Kyorin University School of Medicine, Tokyo, Japan
  • Hada, Ichiro, Kyorin University School of Medicine, Tokyo, Japan
  • Yan, Kunimasa, Kyorin University School of Medicine, Tokyo, Japan
Background

Activation and dysfunction of T-cells underlie the pathogenesis of glomerular diseases including idiopathic nephrotic syndrome. Glucocorticoid (GC) is one of the major classes of drugs that target such T-cells; however, GC-dependence and resistance during the treatment are big issues to be solved. We previously reported that GC-induced transcript 1 (GLCCI1) of thymic T-cells is up-regulated through a GC-GC receptor cascade, bound to dynein-LC8, and phosphorylated by protein kinase-1, and its up-regulation is observed with the activation of a GC-induced apoptotic pathway (ASN meeting 2013). The aim of the present study is to determine the effect of GLCCI1 on T-cell apoptosis induced by GC.

Methods

Using a mouse thymocyte cell line, the GLCCI1 gene was knocked down by lentiviral sh-RNA delivery. Transgenic mice conditionally expressing human GLCCI1 were established using G57BL/6J mice and the tamoxifen-inducible CreER-LoxP system (glcci1-TG/Cre mice). Protein samples from thymocyte cell lines and thymi from mice were subjected to immunoblotting for caspases and Bim to compare the activation of apoptotic signaling. Thymi were analyzed to compare cell number, cell population and organ size between transgenic and non-transgenic mice (glcci1-TG mice).

Results

Immunoblotting for caspases and Bim in the samples from thymocyte cell lines revealed that knock-down of GLCCI1 activated the apoptotic pathway. The size of thymi was significantly larger in glcci1-TG/Cre mice compared to glcci1-TG mice. Cell number of thymi was increased in glcci1-TG/Cre mice compared to that in glcci1-TG mice, whereas there was no significant change in the ratio of T-cell subpopulations between these mice. Finally, immunoblotting for caspases and Bim revealed an apparent reduction of apoptotic signaling in thymi of glcci1-TG/Cre mice compared to glcci1-TG mice.

Conclusion

Although GC is known to cause T-cell death, the results of the present study indicate that GC-induced up-regulation of GLCCI1 limits apoptosis. Therefore, GLCCI1 may be a novel therapeutic target to overcome GC dependence and resistance.