Tnfaip8 is an essential gene for the regulation of glucocorticoid-mediated apoptosis of thymocytes

Abstract

Glucocorticoids have significant immunoregulatory actions on thymocytes and T cells and act by binding and activating cytosolic glucocorticoid receptors, which translocate to the nucleus and control gene expression through binding to specific response elements in target genes. Glucocorticoids promote cell death by activating an apoptotic program that requires transcriptional regulation. We set out to identify genes that are crucial to the process of glucocorticoid-mediated thymocyte apoptosis. Freshly isolated murine primary thymocytes were treated with dexamethasone, mRNA isolated and used to screen DNA microarrays. A set of candidate genes with upregulated expression was identified and selected members assayed in reconstituted fetal thymic organ culture (FTOC). Fetal liver-derived hematopoietic progenitor cells (HPCs) were infected with retroviruses expressing individual genes then used to repopulate depleted fetal thymic lobes. Reconstituted FTOCs expressing the gene Tnfaip8 were treated with dexamethasone and shown to be greatly sensitized to dexamethasone. Retrovirus-mediated RNA interference was applied to knock down Tnfaip8 expression in HPCs and these were used to reconstitute FTOCs. We observed that downregulating the expression of Tnfaip8 alone was sufficient to effectively protect thymocytes against glucocorticoid-induced apoptosis. We propose that Tnfaip8 is crucial in regulating glucocorticoid-mediated apoptosis of thymocytes.

Regulation of inflammation and tumorigenesis by the TIPE family of phospholipid transfer proteins

“…39 In contrast to the aforementioned studies, the downregulation of TNFAIP8 has also been shown to prevent glucocorticoid-mediated apoptosis in thymocytes. 40 TIPE1 is an enhancer of apoptosis TIPE1, also known as Oxi-β, was first characterized in 2011 after the development of a specific antibody to this protein. In mice, TIPE1 was found to be expressed in a wide variety of tissues, including neurons, hepatocytes, muscle tissue, intestinal epithelial cells and germ cells, but surprisingly, it was absent from mature B and T cells.…”

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

“…A critical role for a novel factor, tumor necrosis factor alphainduced protein 8 (TNFAIP8) in glucocorticoidsinduced thymocyte apoptosis was recently identified. TNFAIP8 contains a death effector domain (DED) [38] . MicroRNA bioprocessing plays an important role in glucocorticoids -induced apoptosis in lymphocytes [39] .…”

Genome-wide transcriptome analysis of dendritic cells in a model of acute and persistent infection

“…In thymocytes, the down regulation of TNFAIP8 effectively protected the cells against glucocorticoid induced apoptosis [130]. Furthermore, the decreased expression level of TNFAIP8 establishes the significantly enhanced level of pro-inflammatory effector molecules such as CXCL8, IL-6, CCL1 and IL-17A [67], which is in good agreement with our observations, showing a reversible expression of TNFAIP8 with the aforementioned pro-inflammatory molecules.…”

“…TNFAIP8 is also an essential negative regulator of inflammation and immune homeostasis by down regulating the T cell receptor and TLR signaling [67] and, as it was mentioned earlier, down regulation of this gene is involved in the protection against apoptosis [130]. To the best of our knowledge we were the first who demonstrated the significant down regulation of TNFAIP8 in psoriatic dermis and epidermis at a relative gene expression level which in accordance with the literature explains the enhanced cytokine production and the decreased sensitivity to pro-apoptotic processes which is characteristic for psoriasis.…”