Platelet-activating factor, a molecular sensor for cellular damage, activates systemic immune suppression.
Ultraviolet (UV) radiation plays a critical role in the induction of nonmelanoma skin cancer. UV radiation is also immune suppressive, and the immune suppression induced by UV irradiation has been identified as a major risk factor for skin cancer induction. Previously, we showed that UV exposure activates a cytokine cascade involving prostaglandin (PG)E(2), interleukin (IL)-4, and IL-10 that induces immune suppression. However, the earliest molecular events that occur immediately after UV exposure, especially those upstream of PGE2, are not well defined. UV-irradiated keratinocytes secrete the inflammatory phospholipid mediator, platelet-activating factor (PAF). Because PAF upregulates the production of immunomodulatory compounds, including PGE2, we tested the hypothesis that UV-induced PAF activates cytokine production and initiates UV-induced immune suppression. Both UV and PAF activated cyclooxygenase (COX)-2 and IL-10 reporter gene construct transcription. PAF mimicked the effects of UV in vivo and suppressed delayed-type hypersensitivity (DTH). Furthermore, immune suppression was blocked when UV-irradiated mice were injected with PAF receptor antagonists. In addition to the well-known role of PAF as a proinflammatory lipid mediator, we propose that the PAF receptor senses cellular damage through the recognition of PAF and/or PAF-like molecules, such as oxidized phosphatidylcholine, which activates cytokine transcription and induces systemic immune suppression.
Walterscheid
Jeffrey P
JP
Department of Immunology, The University of Texas, M.D. Anderson Cancer Center, and the Graduate School of Biomedical Sciences, Houston, Texas 77030-4009, USA.
Ullrich
Stephen E
SE
Nghiem
Dat X
DX
D000818:Animals; D051546:Cyclooxygenase 2; D004789:Enzyme Activation / Q000528:radiation effects; D007165:Immunosuppression Therapy; D007527:Isoenzymes / Q000276:immunology / Q000378:metabolism; D015603:Keratinocytes / Q000276:immunology* / Q000378:metabolism / Q000528:radiation effects; D051379:Mice; D008809:Mice, Inbred C3H; D010972:Platelet Activating Factor / Q000276:immunology* / Q000378:metabolism; D010980:Platelet Membrane Glycoproteins / Q000276:immunology / Q000378:metabolism; D011451:Prostaglandin-Endoperoxide Synthases / Q000276:immunology / Q000378:metabolism; D011956:Receptors, Cell Surface; D043562:Receptors, G-Protein-Coupled; D018123:Receptors, Interleukin / Q000096:biosynthesis / Q000276:immunology; D053701:Receptors, Interleukin-10; D015398:Signal Transduction / Q000276:immunology; D014158:Transcription, Genetic / Q000528:radiation effects; D014466:Ultraviolet Rays
D007527:Isoenzymes; D010972:Platelet Activating Factor; D010980:Platelet Membrane Glycoproteins; D011956:Receptors, Cell Surface; D043562:Receptors, G-Protein-Coupled; D018123:Receptors, Interleukin; D053701:Receptors, Interleukin-10; C039351:platelet activating factor receptor; D051546:Cyclooxygenase 2; D011451:Prostaglandin-Endoperoxide Synthases