Phytosphingosine derivatives ameliorate skin inflammation by inhibiting NF-κB and JAK/STAT signaling in keratinocytes and mice

J Invest Dermatol. 2014 Apr;134(4):1023-1032. doi: 10.1038/jid.2013.453. Epub 2013 Oct 31.


Phytosphingosine is abundant in plants and fungi and is found in mammalian epidermis, including the stratum corneum. Phytosphingosine and its derivatives N-acetyl phytosphingosine and tetraacetyl phytosphingosine are part of the natural defense system of the body. However, these molecules exhibit strong toxicities at high concentrations. We synthesized phytosphingosine derivatives, mYG-II-6 ((Z)-4-oxo-4-(((2S,3S,4R)-1,3,4-trihydroxyoctadecan-2-yl)amino)but-2-enoic acid) and fYG-II-6 ((E)-4-oxo-4-(((2S,3S,4R)-1,3,4-trihydroxyoctadecan-2-yl)amino)but-2-enoic acid), to increase efficacy and decrease toxicity, and the biological activities of the derivatives in the inflammatory response were examined. Both YG-II-6 compounds effectively suppressed 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced inflammatory skin damage and inflammatory response in a mouse model. In addition, topical application of fYG-II-6 suppressed ear swelling and psoriasiform dermatitis in the ears of IL-23-injected mice. Anti-inflammatory and antipsoriatic activities of the phytosphingosine derivatives inhibited NF-κB, JAK/signal transducer and activator of transcription (JAK/STAT), and mitogen-activated protein kinase (MAPK) signaling. Finally, the YG-II-6 compounds induced programmed cell death in keratinocytes and mouse skin and were less toxic than phytosphingosine. Our study demonstrated that the phytosphingosine-derived YG-II-6 compounds have much stronger biological potencies than the lead compounds. The YG-II-6 compounds ameliorated inflammatory skin damage. Thus, YG-II-6 compounds are potential topical agents for treating chronic inflammatory skin diseases, such as psoriasis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Animals
  • Anti-Inflammatory Agents / chemistry
  • Apoptosis
  • Cell Survival
  • Dermatitis / metabolism
  • Humans
  • Inflammation / drug therapy*
  • Interleukin-23 / metabolism
  • Janus Kinase 1 / antagonists & inhibitors
  • Janus Kinase 1 / metabolism*
  • Keratinocytes / cytology*
  • Keratinocytes / drug effects
  • Leukocytes, Mononuclear / cytology
  • MAP Kinase Signaling System
  • Male
  • Mice
  • NF-kappa B / antagonists & inhibitors
  • NF-kappa B / metabolism*
  • Psoriasis / metabolism
  • Signal Transduction
  • Skin / drug effects
  • Skin / metabolism*
  • Skin / pathology
  • Sphingosine / analogs & derivatives*
  • Sphingosine / chemistry
  • T-Lymphocytes / cytology
  • Tetradecanoylphorbol Acetate / chemistry


  • Anti-Inflammatory Agents
  • Interleukin-23
  • NF-kappa B
  • Janus Kinase 1
  • phytosphingosine
  • Sphingosine
  • Tetradecanoylphorbol Acetate