Evaluation of the potential role of cytokines in toxic epidermal necrolysis.
Toxic epidermal necrolysis is a rare disease observed as a consequence of adverse reactions to drugs. It results in the widespread apoptosis of epidermal cells and has a high mortality rate. The mechanisms leading to this apoptosis are not yet elucidated. We investigated whether the cytokines present in the blister fluid, which accumulates under necrotic epidermis, originated from T lymphocytes and may play a role in the propagation of keratinocyte apoptosis. Interferon gamma (IFN-gamma), soluble tumor necrosis factor alpha (TNF-alpha), soluble Fas ligand (sFas-L) were present in much higher concentration in the blister fluids of 13 toxic epidermal necrolysis (TEN) patients than in control fluids from burns. The results of RT-PCR studies, however, indicated that only IFN-gamma and to a lesser extent interleukin (IL)-18 were produced by mononuclear cells present in the fluid. That suggests that the other cytokines also present (TNF-alpha, sFas-L, IL-10) rather originated from activated keratinocytes. Fas-L was indeed overexpressed on the membranes of keratinocytes in lesional skin in situ. The Th1 profile of T lymphocyte activation found in the blister fluid of patients with TEN is consistent with a key role for drug-specific cytotoxic T lymphocytes (CTL) as previously reported, the activation of keratinocytes by IFN-gamma making them sensitive to cell-mediated cytolysis. We propose the hypothesis that the production of Fas-L, TNF-alpha, and IL-10 by keratinocytes could be a defense mechanism against CTL rather than a way of propagating apoptosis among epidermal cells.
Nassif
Amal
A
Inserm U 448, Hôpital Henri Mondor, Université Paris XII, Créteil, France.
Moslehi
Homayoun
H
Le Gouvello
Sabine
S
Bagot
Martine
M
Lyonnet
Luc
L
Michel
Laurence
L
Boumsell
Laurence
L
Bensussan
Armand
A
Roujeau
Jean-Claude
JC
D017209:Apoptosis; D001768:Blister / Q000276:immunology / Q000378:metabolism; D001826:Body Fluids / Q000276:immunology / Q000378:metabolism; D002056:Burns / Q000276:immunology / Q000378:metabolism; D016207:Cytokines / Q000276:immunology* / Q000378:metabolism; D053222:Fas Ligand Protein; D006801:Humans; D016753:Interleukin-10 / Q000276:immunology / Q000378:metabolism; D020382:Interleukin-18 / Q000276:immunology / Q000378:metabolism; D015603:Keratinocytes / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D008562:Membrane Glycoproteins / Q000276:immunology / Q000378:metabolism; D013262:Stevens-Johnson Syndrome / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D013601:T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology / Q000378:metabolism; D019014:fas Receptor / Q000276:immunology / Q000378:metabolism
D016207:Cytokines; C505661:FASLG protein, human; D053222:Fas Ligand Protein; D020382:Interleukin-18; D008562:Membrane Glycoproteins; D014409:Tumor Necrosis Factor-alpha; D019014:fas Receptor; D016753:Interleukin-10