Understanding the connection between platelet-activating factor, a UV-induced lipid mediator of inflammation, immune suppression and skin cancer

Abstract

Lipid mediators of inflammation play important roles in several diseases including skin cancer, the most prevalent type of cancer found in the industrialized world. Ultraviolet (UV) radiation is a complete carcinogen and is the primary cause of skin cancer. UV radiation is also a potent immunosuppressive agent, and UV-induced immunosuppression is a well-known risk factor for skin cancer induction. An essential mediator in this process is the glyercophosphocholine 1-alkyl-2-acetyl-sn-glycero-3-phosphocholine commonly referred to as platelet-activating factor (PAF). PAF is produced by keratinocytes in response to diverse stimuli and exerts its biological effects by binding to a single specific G-protein-coupled receptor (PAF-R) expressed on a variety of cells. This review will attempt to describe how this lipid mediator is involved in transmitting the immunosuppressive signal from the skin to the immune system, starting from its production by keratinocytes, to its role in activating mast cell migration in vivo, and to the mechanisms involved that ultimately lead to immune suppression. Recent findings related to its role in regulating DNA repair and activating epigenetic mechanisms, further pinpoint the importance of this bioactive lipid, which may serve as a critical molecular mediator that links the environment (UVB radiation) to the immune system and the epigenome.

Fig. 1

Structure of platelet activating factor. Structural features of PAF include: (1) an ether bond at the sn-1 position. (2) Acetic acid esterified to glycerol at sn-2. (3) Phosphocholine head group at sn-3.

Fig. 2

Essential steps in PAF biosynthesis: The remodeling pathway. Step 1: generation of Lyso-PAF. Step 2: Acetylation of Lyso-PAF. See Section 2 for details.

Fig. 3

The de novo synthesis of PAF. Step 1: acetylation of 1-akyl-2-lyso-sn-glycero-3-P by acetyl-CoA-alkyl-lysoglycero-P acetyltransferase. Step 2: Dephosphorylation of 1-alkyl-2-sn-glycero-3-P to form 1-aklyl-2-lyso-sn-glycerol. Step 3: Transfer of phosphocholine from CDP-Choline to form PAF. The availability of CDP-choline appears to be the rate-limiting factor in the de novo synthesis of PAF.

Fig. 4

Potential mechanisms that transmit the immune suppressive signal contained within UVB radiation to the immune system. The epidermis is the outermost layer of the skin comprised mostly of keratinocytes. Most of the UVB energy is absorbed here. Keratinocyte-derived PAF activates the up regulation of CXCR4 on dermal mast cells. PAF-induced histone acetylation of the CXCR4 promoter appears to be involved. This activates mast cell migration from the skin to the draining lymph nodes, where they secrete IL-10 and suppress CHS and antibody production. UV damaged keratinocytes also up-regulate RANK-L, which re-programs migrating Langerhans cells (LC) to activate T regulatory cells. This figure is modified from an image produced by The National Institutes of Health (Don Bliss artist, ID # 4606), which is in the public domain and can be freely reused.