Wnt-4 Protects Thymic Epithelial Cells Against Dexamethasone-Induced Senescence

Abstract

Glucocorticoids are widely used immunosuppressive drugs in treatment of autoimmune diseases and hematological malignancies. Glucocorticoids are particularly effective immune suppressants, because they induce rapid peripheral T cell and thymocyte apoptosis resulting in impaired T cell-dependent immune responses. Although glucocorticoids can induce apoptotic cell death directly in developing thymocytes, how exogenous glucocorticoids affect the thymic epithelial network that provides the microenvironment for T cell development is still largely unknown. In the present work, we show that primary thymic epithelial cells (TECs) express glucocorticoid receptors and that high-dosage dexamethasone induces degeneration of the thymic epithelium within 24 h of treatment. Changes in organ morphology are accompanied by a decrease in the TEC transcription factor FoxN1 and its regulator Wnt-4 parallel with upregulation of lamina-associated polypeptide 2a and peroxisome proliferator activator receptor g, two characteristic molecular markers for adipose thymic involution. Overexpression of Wnt-4, however, can prevent upregulation of adipose differentiation-related aging markers, suggesting an important role of Wnt-4 in thymic senescence.

Central Immune Senescence, Reversal Potentials

“…Both Wnt4 and FoxN1 levels were measured drastically down-regulated, while the adipocyte differentiation factor ADRP, down-stream target of PPAR was significantly increased. The results indicate that adipocyte-type trans-differentiation is completed at the molecular level over a much shorter time period following exogenous steroid-induced senescence compared to physiological rate senescence (Talaber et al 2011). …”

“…While in the control cell line DX exposure induced up-regulation of adipose trans-differentiation markers, within the Wnt4 over-expressing cell line, none of the adipose trans-differentiation markers were upregulated indicating that Wnt4 alone can efficiently protect TECs against exogenous steroidinduced adipose trans-differentiation (Talaber et al 2011). …”

“…Similar to physiological senescence, the level of FoxN1 transcription factor and its regulator Wnt4 decreased in TECs within 24 hours following a single dose DX injection and remained low for over 1 week (Talaber et al 2011). …”

Histological and Immunohistochemical Study on the Effect of Constant Light Exposure on T Lymphocyte Subsets in the Thymus and Lymph Node of Male Albino Rats

“…Many degenerated thymic epithelial reticular cells were noticed after constant light exposure. This might be due to accelerated thymic epithelial aging caused by glucocorticoids [41] . Low level of melatonin affects functions of thymic epithelial cells.…”

Thymic epithelial cell development and differentiation: cellular and molecular regulation

“…With ageing, the expression of Wnt4 and its downstream target gene Foxn1 are down-regulated. Another Wnt4 target gene, connective tissue growth factor (CTGF) is potentially involved in a negative feed-back loop suppressing Wnt expression, which is important for initiation of thymic senescence (Varecza et al, 2011).…”