Seitz, Carina
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The orphan nuclear receptor LRH-1/NR5a2 critically regulates T cell functions
LRH-1 (liver receptor homolog-1/NR5a2) is an orphan nuclear receptor, which regulates glucose and lipid metabolism, as well as intestinal inflammation via the transcriptional control of intestinal glucocorticoid synthesis. Predominantly expressed in epithelial cells, its expression and role in immune cells are presently enigmatic. LRH-1 was found to be induced in immature and mature T lymphocytes upon stimulation. T cell-specific deletion of LRH-1 causes a drastic loss of mature peripheral T cells. LRH-1-depleted CD4+ T cells exert strongly reduced activation-induced proliferation in vitro and in vivo and fail to mount immune responses against model antigens and to induce experimental intestinal inflammation. Similarly, LRH-1-deficient cytotoxic CD8+ T cells fail to control viral infections. This study describes a novel and critical role of LRH-1 in T cell maturation, functions, and immopathologies and proposes LRH-1 as an emerging pharmacological target in the treatment of T cell-mediated inflammatory diseases.
Inhibitor of Apoptosis Protein-1 Regulates Tumor Necrosis Factor-mediated Destruction of Intestinal Epithelial Cells
Background and aims
Tumor necrosis factor (TNF) is a cytokine that promotes inflammation and contributes to pathogenesis of inflammatory bowel diseases. Unlike other cells and tissues, intestinal epithelial cells undergo rapid cell death upon exposure to TNF, by unclear mechanisms. We investigated the roles of inhibitor of apoptosis proteins (IAPs) in the regulation of TNF-induced cell death in the intestinal epithelium of mice and intestinal organoids.
Methods
RNA from cell lines and tissues and analyzed by quantitative PCR, protein levels were analyzed by immunoblot assays. BIRC2 (also called cIAP1) was expressed upon induction from lentiviral vectors in young adult mouse colon (YAMC) cells. YAMC cells, the mouse colon carcinoma cell line MC38, the mouse macrophage cell line RAW 264.7, or mouse and human organoids were incubated with Smac-mimetic compound LCL161 or recombinant TNF-like weak inducer of apoptosis (TNFSF12) along with TNF, and cell death was quantified. C57BL/6 mice with disruption of Xiap,Birc2 (encodes cIAP1), Birc3 (encodes cIAP2), Tnfrsf1a, or Tnfrsf1b (Tnfrsf1a and b encode TNF receptors) were injected with TNF or saline (control); liver and intestinal tissues were collected and analyzed for apoptosis induction by cleaved caspase 3 immunohistochemistry. We also measured levels of TNF and alanine aminotransferase in serum from mice.
Results
YAMC cells, and mouse and human intestinal organoids, died rapidly in response to TNF. YAMC and intestinal crypts expressed lower levels of XIAP, cIAP1, cIAP2, and cFLIP than liver tissue. Smac-mimetics reduced levels of cIAP1 and XIAP in MC38 and YAMC cells, and Smac-mimetics and TWEAK increased TNF-induced cell death in YAMC cells and organoids—most likely by sequestering and degrading cIAP1. Injection of TNF greatly increased levels of cell death in intestinal tissue of cIAP1-null mice, compared to wild-type C57BL/6 mice, cIAP2-null mice, or XIAP-null mice. Excessive TNF-induced cell death in the intestinal epithelium was mediated TNF receptor 1.
Conclusion
In a study of mouse and human cell lines, organoids, and tissues, we found cIAP1 to be required for regulation of TNF-induced intestinal epithelial cell death and survival. These findings have important implications for the pathogenesis of TNF-mediated enteropathies and chronic inflammatory diseases of the intestine.