The platelet-activating factor receptor protects epidermal cells from tumor necrosis factor (TNF) alpha and TNF-related apoptosis-inducing ligand-induced apoptosis through an NF-kappa B-dependent process.
A number of chemical mediators can induce human keratinocytes and epidermal-derived carcinomas to undergo apoptosis, or programmed cell death. Recent evidence suggests pro-inflammatory cytokines, such as interleukin-1 beta or transforming growth factor alpha, protects carcinomas from numerous pro-apoptotic stimuli. Platelet-activating factor (1-alkyl-2-acetyl-3-glycerophosphocholine; PAF) is a lipid mediator with pro-inflammatory effects on numerous cell types. Although PAF can be metabolized to other bioactive lipids, the majority of PAF effects occur through activation of a G protein-coupled receptor. Using a model system created by retroviral transduction of the PAF receptor (PAF-R) into the PAF-R-negative human epidermal cell line KB and the PAF-R-expressing keratinocyte cell line HaCaT, we now demonstrate that activation of the epidermal PAF-R results in protection from apoptosis induced by tumor necrosis factor (TNF) alpha or TNF-related apoptosis-inducing ligand. The PAF-mediated protection was inhibited by PAF-R antagonists, and protection did not occur in PAF-R-negative KB cells. Additionally, we show protection from TNFalpha- or TRAIL-induced apoptosis by PAF-R activation is dependent on the transcription factor nuclear factor (NF)-kappa B, because PAF-R activation-induced NF-kappa B and epidermal cells transduced with a super-repressor form of inhibitor kappa B were not protected by the PAF-R. These studies provide a mechanism whereby the epidermal PAF-R, and possibly other G protein-coupled receptors, can exert anti-apoptotic effects through an NF-kappa B-dependent process.
Southall
M D
MD
Department of Dermatology, Indiana University School of Medicine, Indianapolis, Indiana 46202, USA.
Isenberg
J S
JS
Nakshatri
H
H
Yi
Q
Q
Pei
Y
Y
Spandau
D F
DF
Travers
J B
JB
D017209:Apoptosis / Q000187:drug effects*; D002460:Cell Line; D000078404:Epidermal Cells; D004817:Epidermis / Q000187:drug effects*; D006801:Humans; D008024:Ligands; D016328:NF-kappa B / Q000502:physiology*; D010980:Platelet Membrane Glycoproteins / Q000502:physiology*; D011956:Receptors, Cell Surface; D043562:Receptors, G-Protein-Coupled; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*
D008024:Ligands; D016328:NF-kappa B; D010980:Platelet Membrane Glycoproteins; D011956:Receptors, Cell Surface; D043562:Receptors, G-Protein-Coupled; D014409:Tumor Necrosis Factor-alpha; C039351:platelet activating factor receptor