Tumor necrosis factor alpha up-regulates non-lymphoid Fas-ligand following superantigen-induced peripheral lymphocyte activation.
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 TNFalpha in this feedback regulation. Injection of TNFalpha into mice caused a rapid up-regulation of Fas-ligand mRNA in IEC. TNFalpha-induced activation of the Fas-ligand promoter in IEC requires NF-kappaB as this was blocked by an I-kappaBalphaM super-repressor and by mutation of an NF-kappaB 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 TNFalpha-/- or TNFR1-/- mice. These results define a novel pathway wherein TNFalpha, 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.
Division of Cellular Immunology, La Jolla Institute for Allergy and Immunology, San Diego, California 92121, USA. michael@liai.org
Michael J
MJ
Pinkoski
Nathalie M
NM
Droin
Douglas R
DR
Green
D000818:Animals; D015703:Antigens, CD / Q000502:physiology; D002478:Cells, Cultured; D053222:Fas Ligand Protein; D007413:Intestinal Mucosa / Q000378:metabolism*; D008213:Lymphocyte Activation / Q000502:physiology*; D008562:Membrane Glycoproteins / Q000096:biosynthesis* / Q000235:genetics; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D012333:RNA, Messenger / Q000032:analysis; D018124:Receptors, Tumor Necrosis Factor / Q000502:physiology; D047888:Receptors, Tumor Necrosis Factor, Type I; D018089:Superantigens / Q000276:immunology*; D014409:Tumor Necrosis Factor-alpha / Q000502:physiology*; D015854:Up-Regulation
D015703:Antigens, CD; D053222:Fas Ligand Protein; C505658:Fasl protein, mouse; D008562:Membrane Glycoproteins; D012333:RNA, Messenger; D018124:Receptors, Tumor Necrosis Factor; D047888:Receptors, Tumor Necrosis Factor, Type I; D018089:Superantigens; D014409:Tumor Necrosis Factor-alpha