cis-Urocanic Acid Enhances Prostaglandin E(2) Release and Apoptotic Cell Death via Reactive Oxygen Species in Human Keratinocytes

Kazuyo Kaneko, Susan L. Walker, Joey Lai-Cheong, Mary S. Matsui, Mary Norval, Antony R. Young*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

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 alpha-tocopherol can reduce this ROS generation, subsequent PGE2 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 PGE2 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 alpha-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 PGE2 synthesis and apoptotic cell death.

Original languageEnglish
Pages (from-to)1262-1271
Number of pages10
JournalJournal of Investigative Dermatology
Volume131
Issue number6
DOIs
Publication statusPublished - Jun 2011

Keywords

  • INDUCED IMMUNE SUPPRESSION
  • IN-VITRO
  • TOPICAL APPLICATION
  • INDUCED OXIDATIVE STRESS
  • UVB-INDUCED IMMUNOSUPPRESSION
  • CONTACT HYPERSENSITIVITY
  • MONOCLONAL-ANTIBODY
  • SYSTEMIC IMMUNOSUPPRESSION
  • ULTRAVIOLET-IRRADIATION
  • GROWTH-FACTOR RECEPTOR

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