title: Phytosphingosine derivatives ameliorate skin inflammation by inhibiting NF-κB and JAK/STAT signaling in keratinocytes and mice.
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.
authors.affiliation: Department of Dermatology, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea.
authors.forename: Byung-Hak
authors.initials: BH
authors.lastname: Kim
authors.affiliation: College of Pharmacy, Seoul National University, Seoul, Republic of Korea.
authors.forename: Ji Min
authors.initials: JM
authors.lastname: Lee
authors.affiliation: College of Pharmacy, Seoul National University, Seoul, Republic of Korea.
authors.forename: Yong-Gyu
authors.initials: YG
authors.lastname: Jung
authors.affiliation: College of Pharmacy, Seoul National University, Seoul, Republic of Korea. Electronic address: tykimder@catholic.ac.kr.
authors.forename: Sanghee
authors.initials: S
authors.lastname: Kim
authors.affiliation: Department of Dermatology, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea.
authors.forename: Tae-Yoon
authors.initials: TY
authors.lastname: Kim
mesh_terms: D000328:Adult; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000737:chemistry; D017209:Apoptosis; D002470:Cell Survival; D003872:Dermatitis / Q000378:metabolism; D006801:Humans; D007249:Inflammation / Q000188:drug therapy*; D053759:Interleukin-23 / Q000378:metabolism; D053613:Janus Kinase 1 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D015603:Keratinocytes / Q000166:cytology* / Q000187:drug effects; D007963:Leukocytes, Mononuclear / Q000166:cytology; D020935:MAP Kinase Signaling System; D008297:Male; D051379:Mice; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000378:metabolism*; D011565:Psoriasis / Q000378:metabolism; D015398:Signal Transduction; D012867:Skin / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D013110:Sphingosine / Q000031:analogs & derivatives* / Q000737:chemistry; D013601:T-Lymphocytes / Q000166:cytology; D013755:Tetradecanoylphorbol Acetate / Q000737:chemistry
chemical_list: D000893:Anti-Inflammatory Agents; D053759:Interleukin-23; D016328:NF-kappa B; D053613:Janus Kinase 1; C012491:phytosphingosine; D013110:Sphingosine; D013755:Tetradecanoylphorbol Acetate