title: Augmentation of chemotherapy-induced cytokine production by expression of the platelet-activating factor receptor in a human epithelial carcinoma cell line.
abstract: In addition to their known cytotoxic effects, chemotherapeutic agents can trigger cytokine production in tumor cells. Moreover, many chemotherapeutic agents are potent pro-oxidative stressors. Although the lipid mediator platelet-activating factor (PAF) is synthesized in response to oxidative stress, and many epidermal carcinomas express PAF receptors (PAF-R) linked to cytokine production, it is not known whether PAF is involved in chemotherapeutic agent-induced cytokine production. These studies examined the role of the PAF system in chemotherapy-mediated cytokine production using a model system created by retroviral-mediated transduction of the PAF-R-negative human epidermal carcinoma cell line KB with the human PAF-R. The presence of the PAF-R in KB cells resulted in augmentation of the production of cytokines IL-8 and TNF-alpha induced by the chemotherapeutic agents etoposide and mitomycin C. These effects were specific for the PAF-R, as expression of the G protein-coupled receptor for fMLP did not affect chemotherapeutic agent-induced cytokine production. Moreover, ablation of the native PAF-R in the epithelial cell line HaCaT using an inducible antisense PAF-R strategy inhibited etoposide-induced cytokine production. Oxidative stress and the transcription factor NF-kappaB were found to be involved in this augmentative effect, because it was mimicked by the oxidant tert-butyl-hydroperoxide, which was blocked both by antioxidants and by inhibition of the NFkappaB pathway using a super-repressor IkappaBM mutant. These studies provide evidence for a novel pathway by which the epidermal PAF-R can augment chemotherapy-induced cytokine production through an NF-kappaB-dependent process.
authors.affiliation: Department of Dermatology, H. B. Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, IN 46202, USA.
authors.forename: Marc
authors.initials: M
authors.lastname: Darst
authors.forename: Mohammed
authors.initials: M
authors.lastname: Al-Hassani
authors.forename: Tao
authors.initials: T
authors.lastname: Li
authors.forename: Qiaofang
authors.initials: Q
authors.lastname: Yi
authors.forename: John M
authors.initials: JM
authors.lastname: Travers
authors.forename: Davina A
authors.initials: DA
authors.lastname: Lewis
authors.forename: Jeffrey B
authors.initials: JB
authors.lastname: Travers
mesh_terms: D000276:Adjuvants, Immunologic / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D000970:Antineoplastic Agents / Q000037:antagonists & inhibitors / Q000494:pharmacology; D000975:Antioxidants / Q000494:pharmacology; D002294:Carcinoma, Squamous Cell / Q000188:drug therapy* / Q000276:immunology* / Q000378:metabolism; D002839:Chromans / Q000494:pharmacology; D016207:Cytokines / Q000037:antagonists & inhibitors / Q000096:biosynthesis*; D005047:Etoposide / Q000037:antagonists & inhibitors / Q000494:pharmacology; D006801:Humans; D016209:Interleukin-8 / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics; D007624:KB Cells; D016685:Mitomycin / Q000494:pharmacology; D016328:NF-kappa B / Q000502:physiology; D018384:Oxidative Stress / Q000187:drug effects; D010742:Phospholipid Ethers / Q000494:pharmacology; D010980:Platelet Membrane Glycoproteins / Q000096:biosynthesis / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D012333:RNA, Messenger / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D043562:Receptors, G-Protein-Coupled / Q000096:biosynthesis / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D015398:Signal Transduction / Q000187:drug effects / Q000276:immunology; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D014161:Transduction, Genetic
chemical_list: D000276:Adjuvants, Immunologic; D000970:Antineoplastic Agents; D000975:Antioxidants; D002839:Chromans; D016207:Cytokines; D016209:Interleukin-8; D016328:NF-kappa B; D010742:Phospholipid Ethers; D010980:Platelet Membrane Glycoproteins; D012333:RNA, Messenger; D043562:Receptors, G-Protein-Coupled; C039351:platelet activating factor receptor; C053479:1-O-hexadecyl-2-N-methylcarbamylphosphatidylcholine; D016685:Mitomycin; D005047:Etoposide; D013755:Tetradecanoylphorbol Acetate; C010643:6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid