Yves Denizota,2~ Laurence Michel b, Jacques Benveniste a,*, Alain Meybeck c, Yolbne Thomas a and. Louis Dubedret D. alNSERM U.200, 92140 Clamart, ...
1093
REVIEW
I
Paf-Acether in Human
Skin I
Yves Denizota,2~ Laurence Michel b, Jacques Benveniste a,*, Alain Meybeck c, Yolbne Thomas a and Louis Dubedret D alNSERM U.200, 92140 Clamart, blNSERM U.312,92010 Cr6teil, and CLVMH Recherche, 92704 Colombes, France
Pal is a phospholipid mediator present in human skin which induces inflammatory events, such as neutrophil infiltration and increased vascular permeability. Recent data suggest that cutaneous cells, such as fibroblasts and keratinocytes, produce pal and that pal is released during allergic cutaneous reactions. It is tempting to speculate that pal may contribute to the development of various skin disorders with acute and chronic skin inflammation. Pal antagonists may help in bringing answers to this hypothesis and may offer new prospects for the treatment of cutaneous inflammatory diseases. Lipids 26, 1093-1094 (1991). Inflammatory reactions commonly observed in human skin have largely been attributed to the action of lipid and peptide mediators, including arachidonlc acid metabolites and paf-acether. Paf-acether (pat) first described as platelet-activating factor (1) and later identified as 1-Oalkyl-2-O-acetyl-sn-glycero-3-phosphocholine (2-4) is one of the most potent mediators of acute allergic and inflammatory reactions (5,6). Pal is synthesized by a wide variety of human inflammatory cells including neutrophils, monocytes, macrophages, platelets, eosinophils, and vascular endothelial cells (7). Pal may also play an important role in the development and maintenance of cutaneous inflammation and in the pathogenesis of inflammatory dermatoses as it produces inflammatory responses in the skin and has been identified in lesional tissue (8,9). For instance, paf has been found in psoriatic scales (10) and has been shown to be associated with primary acquired cold urticaria (11). In human skin, pal is a potent in v i v o agonlst capable of inducing inflammatory events. When locally applied onto human dermis, it increases vascular permeability and neutrophil infiltration (9). When injected intracutaneously, pal elicits a wheal-and-flare response with a perivascular neutrophil infiltrate in normal individuals (8), whereas in allergic patients, a typical hypersensitivity cutaneous reaction occurs associated with an intense eosinophil infiltration (12). Such pal-induced eosinophll recruitment is similar to that induced by antigen in atopic individuals. By using a skin chamber technique in vivo, we recently showed that prolonged contact of allergen with the de~ mis of atopic volunteers induces appearance of paf and intense eosinophil recruitment (13,14). We also observed that, in response to antigen, paf precursors are released in skin chamber fluids from pollen-sensitive patients. In 1Based on a paper presented at the Third International Conference on Platelet~ActivatingFactor and StructurallyRelatedAlkylEther Lipids, Tokyo, Japan, May 1989. 2present address: C.J.F. INSERM 88-03, Facultb de Mbdecine, 2 rue du Docteur Marcland, 87025 Limoges, France. *To whomcorrespondenceshouldbe addressed at INSERM U.200, 32 rue des Carnets, 92140 Clamart, France. Abbreviations: Acetyl-CoA,acetyl-coenzymeA; ILl, interleukin1; lyso pal, lyso paf-acether, 1-O-alkyl-sn-glycer~3-phosphocholine; pal, paf-acether, 1-O-alkyl-2-O-acetyl-sn-glycero-3-phosphocholine.
such patients, paf and its precursors appeared during the late phase of the reaction and persisted for at least 18 hr after the allergen had been removed. The cellular origin of paf is not clear. Inflammatory cells, such as eosinophils, migrating to the inflammatory site in response to the allergen, may produce paf (!2,15). Resident cutaneous cells may also synthesize paf. We recently demonstrated that at least two populations of cutaneous cells, one the fibroblasts in the dermis (16), and the other the keratinocytes in the epidermis (17), produce paf in response to calcium ionophore. Addition of lyso pafacether (lyso pat) to fibroblast cultures enhanced pal synthesis twofold. By contrast, addition of lyso paf to cultured keratinocytes did not modify pal production. However, acetyl-coenzyme A (acetyl-CoA) did enhance epidermal pal production five-fold. During inflammatory reactions, platelets or neutrophils may carry exogenous lyso pal and/or acetate donors to fibroblasts or epidermal cells, thus increasing the production of paf by these cells. At the present time, the physiologic signals that induce fibroblasts or epidermal cells to produce pal are unknown. One possibility is that pal production is induced by cytokines present in the skin such as interleukin 1 (ILl). Epidermal cells secrete ILl in large amounts (18), and ILl induces pal synthesis in endothelial cells (19) and monocytes (20).
CONCLUSION The ability of human epidermal cells and human dermal fibroblasts to generate pal provides additional evidence that pal is a mediator of diverse cellular origin including cells not classically designed as proinflammatory. Paf production by skin may contribute to the development of acute inflammation, to the late allergic response, and to the pathophysiology of various inflammatory dermatoses including psoriasis and cold urticaria.
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