A phytoceramide analog stimulates the production of chemokines through CREB activation in human endothelial cells

Mizuki Sekiya, Kazunori Ueda, Kaori Okazaki, Jun Terashima, Yasuhiro Katou, Haruhisa Kikuchi, Shoichiro Kurata, Yoshiteru Oshima

Research output: Contribution to journalArticlepeer-review

7 Citations (Scopus)

Abstract

Innate immunity is the front-line of self-defense against microbial infection. In mammals, innate immunity interacts with adaptive immunity and has a key role in the regulated immune response. From a pharmaceutical point of view, innate immunity is an ideal target for the development of immunoregulators. Therefore, we aimed to isolate and characterize a novel mammalian immunoregulator isolated from the thermophilic cellulotic fungus Talaromyces sp. 2′-(R)-hydroxy-C 24 phytoceramide (C 24(2′OH)Phy) was isolated from Talaromyces sp. using a Drosophila ex vivo culture system. C 24(2′OH)Phy suppressed the immune deficiency (IMD) pathway-dependent expression of antibacterial peptides in Drosophila, whereas it stimulated the production of chemokines in human cells. Structure activity relationship studies of C 24(2′OH)Phy analogs revealed that both the 2′-(R)-hydroxylignoceroyl group and phytoceramide backbone are essential for the biologic activity of C 24(2′OH)Phy. Microarray analysis revealed that C 24(2′OH)Phy selectively activates the transcription of inflammatory response genes, including chemokines. Furthermore, a reporter gene assay and small interfering RNA analysis demonstrated that C 24(2′OH)Phy stimulates chemokine production through cAMP response element-binding protein activation in human cells. C 24(2′OH)Phy may be a lead immunostimulating compound in humans.

Original languageEnglish
Pages (from-to)1497-1503
Number of pages7
JournalInternational Immunopharmacology
Volume11
Issue number10
DOIs
Publication statusPublished - 2011 Oct 1

Keywords

  • CREB
  • Drosophila
  • Immunomodulator
  • Innate immunity
  • NF-κB
  • Phytoceramide

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology
  • Pharmacology

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