TY - JOUR
T1 - A phytoceramide analog stimulates the production of chemokines through CREB activation in human endothelial cells
AU - Sekiya, Mizuki
AU - Ueda, Kazunori
AU - Okazaki, Kaori
AU - Terashima, Jun
AU - Katou, Yasuhiro
AU - Kikuchi, Haruhisa
AU - Kurata, Shoichiro
AU - Oshima, Yoshiteru
PY - 2011/10/1
Y1 - 2011/10/1
N2 - 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.
AB - 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.
KW - CREB
KW - Drosophila
KW - Immunomodulator
KW - Innate immunity
KW - NF-κB
KW - Phytoceramide
UR - http://www.scopus.com/inward/record.url?scp=80053266745&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=80053266745&partnerID=8YFLogxK
U2 - 10.1016/j.intimp.2011.05.001
DO - 10.1016/j.intimp.2011.05.001
M3 - Article
C2 - 21616176
AN - SCOPUS:80053266745
VL - 11
SP - 1497
EP - 1503
JO - International Immunopharmacology
JF - International Immunopharmacology
SN - 1567-5769
IS - 10
ER -