ISSN:
1365-2133
Source:
Blackwell Publishing Journal Backfiles 1879-2005
Topics:
Medicine
Notes:
Background Apoptosis of keratinocytes or intestinal epithelial cells is an important pathophysiological mechanism of organ damage during acute graft-versus-host disease.Objectives To analyse in detail the mediators and their mutual interaction leading to keratinocyte apoptosis.Methods Experiments were performed using a keratinocyte cell line (HaCaT) and human skin explant cultures.Results Supernatants (SN) of major histocompatibility complex nonmatched mixed lymphocyte cultures (MLCs) induced apoptosis in HaCaT cells and also in keratinocytes from skin biopsies. Although both interferon (IFN)-γ and Fas ligand (FasL) were detected in MLC-SN by enzyme-linked immunosorbent assay, the apoptosis-inducing capacity could be fully abrogated by neutralization of IFN-γ, but not by neutralization of FasL. Recombinant (r) IFN-γ induced HaCaT keratinocyte apoptosis in a dose- and time-dependent manner. Induction of HaCaT apoptosis by rFasL alone was induced only at higher doses than present in MLC-SN, but apoptosis was dramatically enhanced in the presence of rIFN-γ. Further synergistic effects with IFN-γ in the induction of apoptosis were also observed with agonistic antitumour necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) receptor 2 antibody, soluble TRAIL and TNF-α. However, in contrast to FasL and TRAIL, TNF-α alone did not induce HaCaT apoptosis. Interleukin-1β and lipopolysaccharide did not enhance the apoptosis-inducing effect of IFN-γ. Beside its apoptosis-inducing capacity in HaCaT cells, rIFN-γ also induced autocrine IFN-γ production, and combined treatment with IFN-γ and TNF-α induced autocrine TNF-α production. Neutralization of autocrine IFN-γ protected HaCaT cells from apoptosis.Conclusions Taken together, our data suggest a central role for IFN-γ in HaCaT keratinocyte apoptosis but also show the importance of co-acting mediators such as TNF-α, TRAIL and FasL, which potentiate the effect of paracrine and autocrine IFN-γ and TNF-α release.
Type of Medium:
Electronic Resource
URL:
http://dx.doi.org/10.1111/j.1365-2133.2005.06508.x
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