29th Annual Meeting of the American Society of Photobiology

Downtown Marriot

Chicago, Il.

UV activation of a platelet activating factor-like molecule upregulates COX-2 and IL-10 transcription in keratinocytes.

Abstract-
This project tests the hypothesis that ultraviolet (UV)-induced, systemic immune suppression is due to the UV-induced upregulation of cytokine synthesis by keratinocytes. UV irradiation of keratinocytes causes the release of the immunomodulatory compound prostaglandin E2 (PGE2) through the upregulation of cyclooxygenase-2 (COX-2). PGE2 then causes the production and release of serum IL-4 and IL-10. Although it is quite clear that UV-irradiated keratinocytes produce and secrete PGE2 and IL-10, the initial molecular events involved are poorly understood. It is known that keratinocytes express functional platelet activating factor receptors (PAFR) and can produce platelet activating factor (PAF) within minutes of UV-irradiation. However, we have discovered it is possible to mimic the effects of UV exposure by irradiating the common membrane constituent, phosphatidylcholine (PC), and placing it in the media of PAM212 mouse keratinocytes. This causes upregulation of COX-2 and IL-10 promoter construct expression. In addition, the introduction of a PAFR agonist, PCA-4248, abrogates this effect. Furthermore, unirradiated PC does not effect transcription of the reporter gene constructs. The use of a COX-2 specific inhibitor quenches IL-10 transcriptional activation, yet does not lessen the COX-2 transcriptional reporter. We propose that the early events of UV-induced immune suppression entail the photo-degradation of membrane bound PC to form a biologically active analog of PAF. This agonist is sufficient to elicit a signal through the PAFR, which initiates COX-2 transcription. The COX-2 enzyme mediates prostaglandin synthesis, which drives the synthesis of the immunosuppressive modulator IL-10.

Keywords: PAF, COX-2, IL-10