Existence of retinoic acid-receptor-independent retinoid X-receptor-dependent pathway in myeloid cell function.
We previously reported that ER-27191 (4-[4,5,7,8,9,10-hexahydro-7,7,10,10-tetramethyl-1-(3-pyridylmethyl)anthra[1,2-b]pyrrol-3-yl]benzoic acid) is a potent antagonist of retinoic acid receptor (RAR), and ER-35795 ((2E,4E,6E)-7-[1-(1-methylethyl)-8-chloro-1,2,3,4-tetrahydroquinolin-6-yl]-6-fluoro-3-methyl-2,4,6-nonatrienoic acid) is a novel retinoid X receptor (RXR)-specific agonist. By using these compounds, we investigated whether distinct RAR-dependent and RXR-dependent pathways operate to mediate the diverse activities of retinoids, particularly, the effects of the RXR pathway on cellular function. ER-27191 completely antagonized HL60 cell differentiation induced by all-trans-retinoic acid (atRA). However, the differentiation induced by the ER-35795 was not antagonized at all by the RAR antagonist, but was inhibited by an RXR homodimer antagonist (LGD100754, (2E,4E,6Z)-7-(3-n-propoxy-5,6,7,8-tetrahydro-5,5,8,8-tetramethylnaphthalen-2-yl)-3-methylocta-2,4,6-trienoic acid). Its agonistic action on RXR/RAR heterodimer, on the other hand, was neutralized by the RAR antagonist. During HL60 cell differentiation, atRA induced RARbeta mRNA, while the RXR had no effect. Interestingly, a functional RXR-pathway was also seen in lipopolysaccharide-induced inhibition of mouse splenocyte proliferation. These results strongly suggest the existence of a pharmacological RXR-dependent pathway that is activated by a ligand that can bind to RXR.
Tsukuba Research Laboratories for Drug Discovery, Eisai Co., Ltd., Ibaraki, Japan. t-hida@hhc.eisai.co.jp
T
T
Hida
K
K
Tai
N
N
Tokuhara
A
A
Ishibashi
K
K
Kikuchi
S
S
Hibi
H
H
Yoshimura
M
M
Nagai
T
T
Yamauchi
S
S
Kobayashi
D000818:Animals; D000873:Anthracenes / Q000494:pharmacology*; D002454:Cell Differentiation / Q000187:drug effects; D002460:Cell Line; D018922:HL-60 Cells / Q000187:drug effects; D006801:Humans; D051379:Mice; D022423:Myeloid Cells / Q000166:cytology*; D011758:Pyrroles / Q000494:pharmacology*; D011804:Quinolines / Q000494:pharmacology*; D012333:RNA, Messenger / Q000378:metabolism; D018168:Receptors, Retinoic Acid / Q000819:agonists* / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D047488:Retinoid X Receptors; D012176:Retinoids / Q000037:antagonists & inhibitors / Q000494:pharmacology; D013154:Spleen / Q000166:cytology; D013764:Tetrahydronaphthalenes / Q000037:antagonists & inhibitors; D014157:Transcription Factors / Q000819:agonists* / Q000378:metabolism*; D015533:Transcriptional Activation
C113597:4-(4,5,7,8,9,10-hexahydro-7,7,10,10-tetramethyl-1-(3-pyridylmethyl)anthra-(1,2-b)pyrrol-3-yl)benzoic acid; C432463:7-(1-(1-methylethyl)-8-chloro-1,2,3,4-tetrahydroquinolin-6-yl)-6-fluoro-3-methyl-2,4,6-nonatrienoic acid; D000873:Anthracenes; C101596:LG 100754; D011758:Pyrroles; D011804:Quinolines; D012333:RNA, Messenger; D018168:Receptors, Retinoic Acid; D047488:Retinoid X Receptors; D012176:Retinoids; D013764:Tetrahydronaphthalenes; D014157:Transcription Factors