GLUCOCORTICOID INHIBITION OF INTERLEUKIN-1-INDUCED INTERLEUKIN-6 PRODUCTION BY HUMAN LUNG FIBROBLASTS - EVIDENCE FOR TRANSCRIPTIONAL AND POSTTRANSCRIPTIONAL REGULATORY MECHANISMS
Rj. Zitnik et al., GLUCOCORTICOID INHIBITION OF INTERLEUKIN-1-INDUCED INTERLEUKIN-6 PRODUCTION BY HUMAN LUNG FIBROBLASTS - EVIDENCE FOR TRANSCRIPTIONAL AND POSTTRANSCRIPTIONAL REGULATORY MECHANISMS, American journal of respiratory cell and molecular biology, 10(6), 1994, pp. 643-650
Interleukin (IL)-6 is a pleiotropic cytokine produced by a wide variet
y of cells including fibroblasts, macrophages, endothelial cells, and
T and B lymphocytes. Regulated IL-6 production is an important part of
normal biologic homeostasis, and abnormal IL-6 production has been as
sociated with a large number of diseases including asthma and lung all
ograft rejection. Glucocorticoids are potent anti-inflammatory agents
that are widely used to suppress pulmonary inflammation. To further un
derstand the mechanisms underlying this inhibition, we determined whet
her glucocorticoid compounds regulate human lung fibroblast IL-6 produ
ction and characterized the mechanisms of the effects that were noted.
These studies demonstrate that glucocorticoids inhibit IL-1-induced I
L-6 production in a dose-dependent fashion. A greater than 95% decreas
e in IL-6 production was seen with 10(-6) and 10(-7) M dexamethasone,
prednisolone, and hydrocortisone, and IC50 values for these agents wer
e approximately 5 X 10(-10), 5 X 10(-9), and 10(-8) M, respectively. m
RNA analysis demonstrated that these alterations in protein production
were associated with proportionate decreases in IL-6 mRNA accumulatio
n, and that this suppression of IL-6 mRNA could be reversed by the glu
cocorticoid receptor anatagonist RU 486. Nuclear run-on studies demons
trated that glucocorticoids inhibit-IL-1-induced IL-6 gene transcripti
on. However, the magnitude of this effect could not fully account for
the potency of the glucocorticoid-induced alterations in IL-6 mRNA acc
umulation and protein production since 10(-6) M dexamethasone caused o
nly a 50% decrease in IL-1-induced IL-6 gene transcription. mRNA half-
life determinations using the transcription inhibitor actinomycin-D pr
ovided at least a partial explanation for this discrepancy since they
demonstrated that glucocorticoids also selectively destabilize IL-6 mR
NA. When viewed in combination, these studies demonstrate that glucoco
rticoids inhibit lung fibroblast IL-6 production via complex transcrip
tional and post-transcriptional mechanisms that include the inhibition
of IL-6 gene transcription and augmentation of IL-6 mRNA degradation.