Effects of retinoids on the production of tumour necrosis factor-alpha and nitric oxide by lipopolysaccharide-stimulated rat Kupffer cells in vitro: evidence for participation of retinoid X receptor signalling pathway.
Kupffer cells play important roles in the development of liver injury by producing cytokines and free radicals. In consequence inhibition of these inflammatory mediators will be one of the targets for treating liver diseases. Retinoids modulate a wide variety of functions of monocytes/macrophages. Cellular effects of retinoids are mediated by two families of nuclear receptors, retinoic acid receptors (RARs) and retinoid X receptors (RXRs). We examined the effects of several kinds of natural and synthetic retinoids on the production of tumour necrosis factor-alpha (TNF-alpha) and nitric oxide (NO) by LPS-stimulated rat Kupffer cells in vitro. Of the various retinoids tested, 9-cis-retinoic acid (9-cis-RA) and Ro 13-6307 which are agonists of both RARs and RXRs, suppressed the production of TNF-alpha and NO in a concentration-dependent fashion, whereas three types of RAR-selective agonists, Ro 13-7410, Ro 40-6055 and Ro 19-0645 did not show any effect. Furthermore, the RAR alpha antagonist, Ro 41-5253, did not prevent the effects induced by 9-cis-RA. The results suggest that these effects of 9-cis RA and Ro 13-6307 were induced by the RXRs-dependent signalling pathway.
Motomura
K
K
Third Department of Internal Medicine, Faculty of Medicine, Kyushu University, Fukuoka, Japan.
Sakai
H
H
Isobe
H
H
Nawata
H
H
D000818:Animals; D001565:Benzoates / Q000494:pharmacology; D002839:Chromans / Q000494:pharmacology; D005231:Fatty Acids, Unsaturated / Q000494:pharmacology; D066298:In Vitro Techniques; D007728:Kupffer Cells / Q000187:drug effects* / Q000378:metabolism*; D008070:Lipopolysaccharides / Q000494:pharmacology*; D008297:Male; D009569:Nitric Oxide / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar; D018168:Receptors, Retinoic Acid / Q000037:antagonists & inhibitors / Q000502:physiology; D000072482:Retinoic Acid Receptor alpha; D047488:Retinoid X Receptors; D012176:Retinoids / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D013723:Teratogens / Q000494:pharmacology; D014157:Transcription Factors / Q000502:physiology; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis* / Q000187:drug effects*
D001565:Benzoates; D002839:Chromans; D005231:Fatty Acids, Unsaturated; D008070:Lipopolysaccharides; C000607073:Rara protein, rat; D018168:Receptors, Retinoic Acid; D000072482:Retinoic Acid Receptor alpha; D047488:Retinoid X Receptors; D012176:Retinoids; D013723:Teratogens; D014157:Transcription Factors; D014409:Tumor Necrosis Factor-alpha; C084904:Ro 41-5253; D009569:Nitric Oxide; C077135:Ro 13-6307