title: The environmental stressor ultraviolet B radiation inhibits murine antitumor immunity through its ability to generate platelet-activating factor agonists.
abstract: Ubiquitous pro-oxidative stressor ultraviolet B radiation (UVB) to human or mouse skin generates platelet-activating factor (PAF) and novel oxidatively modified glycerophosphocholines (Ox-GPCs) with PAF-receptor (PAF-R) agonistic activity. These lipids mediate systemic immunosuppression in a process involving IL-10. The current studies sought to determine the functional significance of UVB-mediated systemic immunosuppression in an established model of murine melanoma. We show that UVB irradiation augments B16F10 tumor growth and is dependent on host, but not melanoma cell; PAF-R-expression as UVB or the PAF-R agonist, carbamoyl PAF (CPAF), both promote B16F10 tumor growth in wild-type (WT) mice, independent of whether B16F10 cells express PAF-Rs, but do not augment tumor growth in Pafr -/- mice. UVB-mediated augmentation of experimental murine tumor growth was inhibited with antioxidants, demonstrating the importance of Ox-GPC PAF-R agonists produced non-enzymatically. Host immune cells are required as CPAF-induced augmentation of tumor growth which is not seen in immunodeficient NOD SCID mice. Finally, depleting antibodies against IL-10 in WT mice or depletion of CD25-positive cells in FoxP3(EGFP) transgenic mice block UVB and/or CPAF-induced tumor growth supporting a requirement for IL-10 and Tregs in this process. These findings indicate that UVB-generated Ox-GPCs with PAF-R agonistic activity enhance experimental murine melanoma tumor growth through targeting host immune cells, most notably Tregs, to mediate systemic immunosuppression.
authors.affiliation: Department of Dermatology, Indiana University School of Medicine, 1044 Walnut St. Rm. 202, Indianapolis, IN 46202, USA.
authors.forename: Ravi P
authors.initials: RP
authors.lastname: Sahu
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Turner
authors.forename: Sonia C
authors.initials: SC
authors.lastname: DaSilva
authors.forename: Badri M
authors.initials: BM
authors.lastname: Rashid
authors.forename: Jesus A
authors.initials: JA
authors.lastname: Ocana
authors.forename: Susan M
authors.initials: SM
authors.lastname: Perkins
authors.forename: Raymond L
authors.initials: RL
authors.lastname: Konger
authors.forename: Christopher E
authors.initials: CE
authors.lastname: Touloukian
authors.forename: Mark H
authors.initials: MH
authors.lastname: Kaplan
authors.forename: Jeffrey B
authors.initials: JB
authors.lastname: Travers
mesh_terms: D000818:Animals; D008546:Melanoma, Experimental / Q000276:immunology* / Q000473:pathology; D051379:Mice; D010972:Platelet Activating Factor / Q000819:agonists*; D060888:Real-Time Polymerase Chain Reaction; D050378:T-Lymphocytes, Regulatory / Q000276:immunology; D014466:Ultraviolet Rays
chemical_list: D010972:Platelet Activating Factor