Arachidonic acid and its metabolites regulate many key functions in the repair of skin injury, such as vasodilation, chemotaxis, and immunomodulation. Ultraviolet light B (UVB) exposure is a particularly common form of skin injury, which is associated with increased synthesis of eicosanoids. The mechanisms of enhanced synthesis are poorly understood. Recent data obtained in my laboratory indicate that endogenous release of histamine in human skin explants mediates 60% of the increased prostaglandin synthesis in the early period (up to 8 hours) after UV exposure. Studies of epidermal cultures indicate that UV-induced potentiation of histamine-stimulated prostaglandin synthesis involves an increase in the cellular capacity for prostaglandin synthesis, an increase in sensitivity to histamine and calcium influx. However, these UV-induced events must result from photochemical reactions in epidermis. We propose to test the hypothesis that peroxidative injury by UV light increases release of esterified fatty acids through the action of phospholipases A2 and C with consequent activation of protein kinase C. Preliminary data clearly suggest that protein kinase C activation has occurred in UV-injured keratinocytes. In addition, we propose that the normal calcium compartmentalization present in skin is disrupted in UV injury, increasing the availability of calcium to potentiate agonist- induced prostaglandin release. The agonist histamine, which we know stimulates prostaglandin synthesis, and which preliminary data show is synthesized by keratinocytes in UV injury, will be used to dissect these mechanisms. The long-term objective of these studies is to provide the necessary foundation to develop therapy for UVB-induced skin injury. This objective is based on the hypothesis that mechanisms leading to enhanced PGE2 synthesis are important in the pathogenesis of UVB injury.

National Institute of Health (NIH)
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Research Project (R01)
Project #
Application #
Study Section
General Medicine A Subcommittee 2 (GMA)
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Washington University
Schools of Medicine
Saint Louis
United States
Zip Code
Rys-Sikora, Krystyna E; Pentland, Alice P; Konger, Raymond L (2003) Pertussis toxin-sensitive secretory phospholipase A2 expression and motility in activated primary human keratinocytes. J Invest Dermatol 120:86-95
Konger, Raymond L; Scott, Glynis A; Landt, Yvonne et al. (2002) Loss of the EP2 prostaglandin E2 receptor in immortalized human keratinocytes results in increased invasiveness and decreased paxillin expression. Am J Pathol 161:2065-78
Rys-Sikora, K E; Konger, R L; Schoggins, J W et al. (2000) Coordinate expression of secretory phospholipase A(2) and cyclooxygenase-2 in activated human keratinocytes. Am J Physiol Cell Physiol 278:C822-33
Pentland, A P; Schoggins, J W; Scott, G A et al. (1999) Reduction of UV-induced skin tumors in hairless mice by selective COX-2 inhibition. Carcinogenesis 20:1939-44
Chen, X; Gresham, A; Morrison, A et al. (1996) Oxidative stress mediates synthesis of cytosolic phospholipase A2 after UVB injury. Biochim Biophys Acta 1299:23-33
Gresham, A; Masferrer, J; Chen, X et al. (1996) Increased synthesis of high-molecular-weight cPLA2 mediates early UV-induced PGE2 in human skin. Am J Physiol 270:C1037-50
Malaviya, R; Morrison, A R; Pentland, A P (1996) Histamine in human epidermal cells is induced by ultraviolet light injury. J Invest Dermatol 106:785-9
Miller, C C; Hale, P; Pentland, A P (1994) Ultraviolet B injury increases prostaglandin synthesis through a tyrosine kinase-dependent pathway. Evidence for UVB-induced epidermal growth factor receptor activation. J Biol Chem 269:3529-33
Okada, N; Pentland, A P; Falk, P et al. (1994) M protein and protein F act as important determinants of cell-specific tropism of Streptococcus pyogenes in skin tissue. J Clin Invest 94:965-77
Kang-Rotondo, C H; Miller, C C; Morrison, A R et al. (1993) Enhanced keratinocyte prostaglandin synthesis after UV injury is due to increased phospholipase activity. Am J Physiol 264:C396-401

Showing the most recent 10 out of 13 publications