Tumor Necrosis Factor [alpha] Up-regulates Non-lymphoid Fas-ligand following Superantigen-induced Peripheral Lymphocyte Activation

• Published in: The Journal of biological chemistry 2002-11, Vol.277 (44), p.42380-42385
• Main Authors: Pinkoski, MJ, Droin, N M, Green, DR
• Format: Article
• Language: English
• ISSN: 0021-9258

Members of the tumor necrosis factor (TNF) and TNF receptor families play important roles in inducing apoptosis and mediating the inflammatory response. Activated T lymphocytes can trigger the expression of Fas-ligand on non-lymphoid tissue, such as intestinal epithelial cells (IEC), and this, in turn, can induce apoptosis in the T cells. Here, we examine the role of TNF[alpha] in this feedback regulation. Injection of TNF[alpha] into mice caused a rapid up-regulation of Fas-ligand mRNA in IEC. TNF[alpha]-induced activation of the Fas-ligand promoter in IEC requires NF-[kappa]B as this was blocked by an I-[kappa]B[alpha]M super-repressor and by mutation of an NF-[kappa]B site in the Fas-ligand promoter. Activation of T cells by antigen induced Fas-ligand expression in IEC in vivo in wild type, but not in TNF[alpha]-/- or TNFR1-/- mice. These results define a novel pathway wherein TNF[alpha], produced by activated T cells in the intestine, induce Fas-ligand expression in IEC. This is the first observation that one member of the TNF superfamily mediates the regulation of another family member and represents a potential feedback mechanism controlling lymphocyte infiltration and inflammation in the small intestine.