Retinoic acid inhibition of IL-1-induced IL-6 production by human lung fibroblasts

R. J. Zitnik, R. M. Kotloff, J. Latifpour, T. Zheng, N. L. Whiting, J. Schwalb, J. A. Elias

Research output: Contribution to journalArticlepeer-review

Abstract

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-α, RAR-γ, and RXR-α were present, and RAR-β 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.

Original languageEnglish (US)
Pages (from-to)1419-1429
Number of pages11
JournalJournal of Immunology
Volume152
Issue number3
StatePublished - 1994

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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