title: A phytoceramide analog stimulates the production of chemokines through CREB activation in human endothelial cells.
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.
authors: Graduate School of Pharmaceutical Sciences, Tohoku University, 6-3 Aoba, Aramaki, Aoba-ku, Sendai 980-8578, Japan.
authors: Mizuki
authors: M
authors: Sekiya
authors: Kazunori
authors: K
authors: Ueda
authors: Kaori
authors: K
authors: Okazaki
authors: Jun
authors: J
authors: Terashima
authors: Yasuhiro
authors: Y
authors: Katou
authors: Haruhisa
authors: H
authors: Kikuchi
authors: Shoichiro
authors: S
authors: Kurata
authors: Yoshiteru
authors: Y
authors: Oshima