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

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

The Journal of investigative dermatology (2013-11-02)
Byung-Hak Kim, Ji Min Lee, Yong-Gyu Jung, Sanghee Kim, Tae-Yoon Kim
ABSTRACT

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.

MATERIALS
Product Number
Brand
Product Description

Sigma-Aldrich
Phorbol 12-myristate 13-acetate, ≥99% (TLC), film or powder
Sigma-Aldrich
4α-Phorbol 12-myristate 13-acetate, solid, ≥95% (TLC)
Sigma-Aldrich
PMA, for use in molecular biology applications, ≥99% (HPLC)
Sigma-Aldrich
Phytosphingosine hydrochloride
Sigma-Aldrich
Phorbol 12-myristate 13-acetate, synthetic, ≥98.0% (TLC)
Avanti
N-18:0 Phytosphingosine, Avanti Research - A Croda Brand 860610P, powder
Sigma-Aldrich
D-Sphingosine, synthetic
Avanti
N-02:0 Phytosphingosine, Avanti Research - A Croda Brand 860608P, powder
Avanti
N-24:0(2R-OH) Phytosphingosine, Avanti Research - A Croda Brand 860924P, powder