Retinoic acid inhibition of IL-1-induced IL-6 production by human lung fibroblasts.
IL-6 is a multi-functional cytokine that plays an important role in normal biologic homeostasis and disease pathogenesis. Retinoids are vitamin A analogs that regulate the function of a wide variety of inflammatory and structural cells. To further understand the biology of retinoids and IL-6 we determined whether all-trans-retinoic acid (RA) and other retinoids regulate lung fibroblast IL-6 production. RA did not stimulate fibroblast IL-6 production. Instead, it inhibited the production of IL-6 by IL-1-stimulated cells. This effect was dose-dependent with an IC50 of 10(-7) M RA and significant inhibition being noted with doses of RA as low as 10(-8) M. These inhibitory effects could not be explained by cytotoxicity or a shift in the kinetics of IL-6 production. They also did not appear to involve alterations in the early events in IL-1-induced IL-6 production, because RA inhibited IL-6 production even when added 6 h after IL-1 and RA did not inhibit IL-1 binding to cell surface IL-1 receptors. RA inhibition of IL-6 protein production was associated with a comparable decrease in IL-6 mRNA accumulation and gene transcription. 13-cis-retinoic acid, retinol, retinaldehyde, all-trans etretin, Ro 13-6298, and 9-cis retinoic acid also inhibited IL-1-induced IL-6 production. However, 4-hydroxyphenyl retinamide and etretinate did not share this property. The inhibitory effects of these analogues may be mediated by nuclear retinoic acid receptors as mRNA encoding RAR-alpha, RAR-gamma, and RXR-alpha were present, and RAR-beta was induced by RA in human lung fibroblasts. These studies demonstrate that RA and other retinoid analogs inhibit IL-1-induced IL-6 production and that this effect is analog-specific and, at least partially, transcriptionally mediated.
Zitnik
R J
RJ
Department of Internal Medicine, Yale University School of Medicine, New Haven, CT 06510-8040.
Kotloff
R M
RM
Latifpour
J
J
Zheng
T
T
Whiting
N L
NL
Schwalb
J
J
Elias
J A
JA
D002460:Cell Line; D005347:Fibroblasts / Q000378:metabolism; D015870:Gene Expression / Q000187:drug effects; D006801:Humans; D066298:In Vitro Techniques; D007375:Interleukin-1 / Q000037:antagonists & inhibitors*; D015850:Interleukin-6 / Q000235:genetics / Q000378:metabolism*; D015851:Interleukin-7 / Q000235:genetics; D008168:Lung / Q000166:cytology / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics; D018168:Receptors, Retinoic Acid / Q000235:genetics; D014212:Tretinoin / Q000494:pharmacology*
D007375:Interleukin-1; D015850:Interleukin-6; D015851:Interleukin-7; D012333:RNA, Messenger; D018168:Receptors, Retinoic Acid; D014212:Tretinoin