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-C24 phytoceramide (C24(2′OH)Phy) was isolated from Talaromyces sp. using a Drosophila ex vivo culture system. C24(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 C24(2′OH)Phy analogs revealed that both the 2′-(R)-hydroxylignoceroyl group and phytoceramide backbone are essential for the biologic activity of C24(2′OH)Phy. Microarray analysis revealed that C24(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 C24(2′OH)Phy stimulates chemokine production through cAMP response element-binding protein activation in human cells. C24(2′OH)Phy may be a lead immunostimulating compound in humans.