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Fas/Fas ligand interaction contributes to UV-induced apoptosis in human keratinocytes
M Leverkus1, M Yaar, B A Gilchrest
1Department of Dermatology, Boston University School of Medicine, Massachusetts 02118-2394, USA.
Abstract:
Keratinocytes in human skin undergo apoptosis during various inflammatory processes and after ultraviolet (UV) irradiation. To determine if keratinocyte apoptosis may be mediated by the Fas/APO-1 receptor (CD95), a signal transduction pathway known to initiate programmed cell death of lymphocytes, we investigated Fas expression, modulation, and function in keratinocytes. Keratinocytes constitutively expressed the 2.5- and 1.9-kb Fas transcripts, as well as the 43-kDa Fas protein. Treatment of interferon-gamma-stimulated keratinocytes with Fas agonistic antibody significantly promoted their cell death, indicating that Fas in keratinocytes is functional. UV irradiation induced Fas mRNA expression within 16 to 24 h and Fas protein within 24 h and through 48 h after irradiation. Furthermore, keratinocytes constitutively expressed Fas ligand (FasL) mRNA and protein. UV irradiation induced FasL mRNA as early as 4 h after irradiation and elevated FasL mRNA levels were maintained for at least 24 h postirradiation. Moreover, a FasL neutralizing antibody significantly reduced UV-induced apoptosis of IFN-gamma-treated keratinocytes. Our data strongly suggest that the Fas system contributes to keratinocyte apoptosis in UV-irradiated human skin.
Insights
The Fas receptor system plays a role in programmed cell death (apoptosis) of human skin keratinocytes after UV radiation exposure. This pathway is functional and activated by UV, contributing to skin cell death.
Area of Science:
- Dermatology
- Immunology
- Cell Biology
Background:
- Keratinocytes, the primary cells in human skin, undergo apoptosis during inflammation and UV exposure.
- The Fas/APO-1 receptor (CD95) pathway is a known initiator of programmed cell death in lymphocytes.
Purpose of the Study:
- To investigate the expression, modulation, and function of the Fas receptor system in keratinocytes.
- To determine if the Fas pathway mediates keratinocyte apoptosis after UV irradiation.
Main Methods:
- Investigated Fas and Fas ligand (FasL) mRNA and protein expression in keratinocytes.
- Utilized Fas agonistic antibodies and FasL neutralizing antibodies.
- Exposed keratinocytes to UV irradiation and interferon-gamma (IFN-γ).
Main Results:
- Keratinocytes constitutively express functional Fas transcripts and protein.
- UV irradiation significantly upregulates Fas mRNA and protein expression.
- UV irradiation also induces FasL mRNA expression in keratinocytes.
- FasL neutralizing antibodies reduced UV-induced keratinocyte apoptosis.
Conclusions:
- The Fas system is expressed and functional in keratinocytes.
- UV irradiation activates the Fas pathway in keratinocytes.
- The Fas system significantly contributes to UV-induced keratinocyte apoptosis in human skin.