title: cis-Urocanic acid enhances prostaglandin E2 release and apoptotic cell death via reactive oxygen species in human keratinocytes.
abstract: Urocanic acid (UCA) is a major UVR-absorbing skin molecule that undergoes trans to cis photoisomerization in the epidermis following UVR exposure. Murine studies have established that cis-UCA is an important mediator of UVR-induced immune suppression, but little is known about its signaling pathway. We have previously demonstrated that treatment of normal human epidermal keratinocytes with cis-UCA resulted in increased synthesis of prostaglandin E(2) (PGE(2)) and cell death. Here, using immortalized human keratinocytes, we report that cis-UCA but not trans-UCA generates reactive oxygen species (ROS) in a dose-dependent manner and that the natural antioxidant α-tocopherol can reduce this ROS generation, subsequent PGE(2) release, and apoptotic cell death. Western blot analysis revealed that cis-UCA leads to a transient phosphorylation of EGFR as well as downstream mitogen-activated protein kinases (MAPKs), extracellular signal-regulated kinase (ERK) and p38. Pharmacological inhibition of their activity attenuated PGE(2) release induced by cis-UCA. After transient activation, cis-UCA downregulated EGFR protein expression that corresponded to activation of caspase-3. In addition, pretreatment with α-tocopherol inhibited EGFR downregulation and caspase-3 activation induced by cis-UCA. These results suggest that cis-UCA exerts its effects on human keratinocytes via intracellular ROS generation that modulates EGFR signaling and subsequently induces PGE(2) synthesis and apoptotic cell death.
authors.affiliation: St John's Institute of Dermatology, King's College London School of Medicine, London, UK.
authors.forename: Kazuyo
authors.initials: K
authors.lastname: Kaneko
authors.forename: Susan L
authors.initials: SL
authors.lastname: Walker
authors.forename: Joey
authors.initials: J
authors.lastname: Lai-Cheong
authors.forename: Mary S
authors.initials: MS
authors.lastname: Matsui
authors.forename: Mary
authors.initials: M
authors.lastname: Norval
authors.forename: Antony R
authors.initials: AR
authors.lastname: Young
mesh_terms: D017209:Apoptosis / Q000187:drug effects*; D053148:Caspase 3 / Q000502:physiology; D002478:Cells, Cultured; D051546:Cyclooxygenase 2 / Q000502:physiology; D015232:Dinoprostone / Q000096:biosynthesis*; D066246:ErbB Receptors / Q000187:drug effects / Q000502:physiology; D048049:Extracellular Signal-Regulated MAP Kinases / Q000037:antagonists & inhibitors; D006801:Humans; D015603:Keratinocytes / Q000187:drug effects* / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism*; D014560:Urocanic Acid / Q000494:pharmacology*; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors
chemical_list: D017382:Reactive Oxygen Species; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; D066246:ErbB Receptors; D048049:Extracellular Signal-Regulated MAP Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D053148:Caspase 3; D014560:Urocanic Acid; D015232:Dinoprostone