TY - JOUR
T1 - Fas ligand elicits a caspase-independent proinflammatory response in human keratinocytes
T2 - Implications for Dermatitis
AU - Farley, Sherry M.
AU - Dotson, Anjali D.
AU - Purdy, David E.
AU - Sundholm, Aaron J.
AU - Schneider, Pascal
AU - Magun, Bruce E.
AU - Iordanov, Mihail S.
N1 - Funding Information:
We thank Thanh-Hoai Dinh for the excellent assistance with the tissue culture, Jean-Pascal Josi and Karine Ingold for the preparation and characterization of the FasL proteins employed here, Paul Cook for the invaluable help with the reconstructed human epidermis, and Jürg Tschopp for the gift of the anti-FasL antibody. This work was supported by National Institutes of Health Grants AI059335 and DK066439 (B.E.M.), CA-93718 (M.S.I.), and by grants of the Swiss National Science Foundation including a grant from the NCCR (National Center of Competence in Research) Molecular Oncology to P.S.
PY - 2006/11/15
Y1 - 2006/11/15
N2 - Fas ligand (FasL) causes apoptosis of epidermal keratinocytes and triggers the appearance of spongiosis in eczematous dermatitis. We demonstrate here that FasL also aggravates inflammation by triggering the expression of proinflammatory cytokines, chemokines, and adhesion molecules in keratinocytes. In HaCaT cells and in reconstructed human epidermis (RHE), FasL triggered a NF-κB-dependent mRNA accumulation of inflammatory cytokines (tumor necrosis factor-α, IL-6, and IL-1β), chemokines (CCL2/MCP-1, CXCL1/GROα, CXCL3/GROγ, and CXCL8/IL-8), and the adhesion molecule ICAM-1. Oligomerization of Fas was required both for apoptosis and for gene expression. Inhibition of caspase activity abolished FasL-dependent apoptosis; however, it failed to suppress the expression of FasL-induced genes. Additionally, in the presence of caspase inhibitors, but not in their absence, FasL triggered the accumulation of CCL5/RANTES (regulated on activation normal T cell expressed and secreted) mRNA. Our findings identify a novel proinflammatory role of FasL in keratinocytes that is independent of caspase activity and is separable from apoptosis. Thus, in addition to causing spongiosis, FasL may play a direct role in triggering and/or sustaining inflammation in eczemas.
AB - Fas ligand (FasL) causes apoptosis of epidermal keratinocytes and triggers the appearance of spongiosis in eczematous dermatitis. We demonstrate here that FasL also aggravates inflammation by triggering the expression of proinflammatory cytokines, chemokines, and adhesion molecules in keratinocytes. In HaCaT cells and in reconstructed human epidermis (RHE), FasL triggered a NF-κB-dependent mRNA accumulation of inflammatory cytokines (tumor necrosis factor-α, IL-6, and IL-1β), chemokines (CCL2/MCP-1, CXCL1/GROα, CXCL3/GROγ, and CXCL8/IL-8), and the adhesion molecule ICAM-1. Oligomerization of Fas was required both for apoptosis and for gene expression. Inhibition of caspase activity abolished FasL-dependent apoptosis; however, it failed to suppress the expression of FasL-induced genes. Additionally, in the presence of caspase inhibitors, but not in their absence, FasL triggered the accumulation of CCL5/RANTES (regulated on activation normal T cell expressed and secreted) mRNA. Our findings identify a novel proinflammatory role of FasL in keratinocytes that is independent of caspase activity and is separable from apoptosis. Thus, in addition to causing spongiosis, FasL may play a direct role in triggering and/or sustaining inflammation in eczemas.
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U2 - 10.1038/sj.jid.5700477
DO - 10.1038/sj.jid.5700477
M3 - Article
C2 - 16858424
AN - SCOPUS:33750074486
SN - 0022-202X
VL - 126
SP - 2438
EP - 2451
JO - Journal of Investigative Dermatology
JF - Journal of Investigative Dermatology
IS - 11
ER -