Fas pulls the trigger on psoriasis.
Fas/FasL signaling is best known for induction of apoptosis. However, there is an alternate pathway of Fas signaling that induces inflammatory cytokines, particularly tumor necrosis factor (TNF)-alpha and interleukin (IL)-8. This pathway is prominent in cells that express high levels of anti-apoptotic molecules such as Bcl-xL. Because TNF-alpha is central to the pathogenesis of psoriasis and psoriatic epidermis has a low apoptotic index with high expression of Bcl-xL, we hypothesized that inflammatory Fas signaling mediates induction of psoriasis by activated lymphocytes. Noninvolved skin from psoriasis patients was grafted to beige-severe combined immunodeficiency mice, and psoriasis was induced by injection of FasL-positive autologous natural killer cells that were activated by IL-2. Induction of psoriasis was inhibited by injection of a blocking anti-Fas (ZB4) or anti-FasL (4A5) antibody on days 3 and 10 after natural killer cell injection. Anti-Fas monoclonal antibody significantly reduced cell proliferation (Ki-67) and epidermal thickness, with inhibition of epidermal expression of TNF-alpha, IL-15, HLA-DR, and ICAM-1. Fas/FasL signaling is an essential early event in the induction of psoriasis by activated lymphocytes and is necessary for induction of key inflammatory cytokines including TNF-alpha and IL-15.
Gilhar
Amos
A
Laboratory for Skin Research, Rappaport Building, Technion Faculty of Medicine, P.O. Box 9649, Bat-Galim, Haifa 31096, Israel. fligilhar@matat.health.gov.il
Yaniv
Ron
R
Assy
Bedia
B
Serafimovich
Sima
S
Ullmann
Yehuda
Y
Kalish
Richard S
RS
D019264:Adoptive Transfer; D000818:Animals; D053222:Fas Ligand Protein; D006801:Humans; D007150:Immunohistochemistry; D007694:Killer Cells, Natural / Q000276:immunology*; D008213:Lymphocyte Activation / Q000276:immunology; D008562:Membrane Glycoproteins / Q000276:immunology / Q000378:metabolism*; D051379:Mice; D016513:Mice, SCID; D011565:Psoriasis / Q000276:immunology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000276:immunology*; D016038:Skin Transplantation; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis / Q000276:immunology; D048069:Tumor Necrosis Factors / Q000276:immunology / Q000378:metabolism*; D019014:fas Receptor / Q000276:immunology / Q000378:metabolism*
C505661:FASLG protein, human; D053222:Fas Ligand Protein; C505658:Fasl protein, mouse; D008562:Membrane Glycoproteins; D014409:Tumor Necrosis Factor-alpha; D048069:Tumor Necrosis Factors; D019014:fas Receptor