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Volume 271, Number 28, Issue of July 12, 1996 pp. 16591-16596
©1996 by The American Society for Biochemistry and Molecular Biology, Inc.

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Regulation of Interleukin-8 Gene Expression by Interleukin-1, Osteotropic Hormones, and Protein Kinase Inhibitors in Normal Human Bone Marrow Stromal Cells

(Received for publication, March 16, 1996, and in revised form, April 18, 1996)

From the Division of Bone and Mineral Diseases, Department of Internal Medicine, Washington University School of Medicine, Jewish Hospital, St. Louis, Missouri 63110

Interleukin-8 (IL-8), a potent neutrophil chemotactic peptide that elicits pleiotropic biological effects is secreted in large amounts by normal human osteoblastic and bone marrow osteoprogenitor stromal (HBMS) cells in response to IL-1 and tumor necrosis factor-. In the present study we investigated the regulation of IL-8 gene expression by IL-1, osteotropic hormones, and protein kinase inhibitors in primary cultures of HBMS cells. The treatment of HBMS cells with IL-1 increased the steady-state levels of IL-8 mRNA in a dose- and time-dependent fashion and was detectable within 1 h, reached maximal by 4 h, and remained elevated at 24 h, whereas parathyroid hormone (10⁷ and 10⁸ M) had no effect on IL-8 mRNA. Both synthetic and natural glucocorticoids dexamethasone (10⁷-10¹⁰ M) and hydrocortisone (10⁶-10⁸ M) inhibited IL-1-stimulated IL-8 mRNA expression. The suppressive effect of dexamethasone on IL-1-induced IL-8 mRNA was not observed in the presence of cycloheximide (5 µg/ml), indicating that the dexamethasone-mediated repression of IL-8 gene expression also depends on new protein synthesis. Experiments with actinomycin D demonstrated that IL-8 mRNA is long-lived and that glucocorticoids down-regulate IL-8 gene expression mainly by decreasing the mRNA stability in normal HBMS cells. Furthermore, as determined by nuclear run-on analysis, IL-1 increased the rate of transcription of IL-8 gene and dexamethasone did not affect the IL-1-induced transcription of IL-8. 1-(5-Isoquinolinesulfonyl)-2-methylpiperazine, HCl (50 µM) and staurosporine (1 µM), potent inhibitors of protein kinase C, and genistein (100 µM), a specific protein tyrosine kinase inhibitor blocked IL-1-induced IL-8 gene expression. Because curcumin (20 µM), an inhibitor of c-jun/AP-1 and protein kinases, also blocked IL-1-stimulated IL-8 gene expression implicating c-JUN/AP-1 and protein phosphorylation in the induction of IL-8 gene expression by IL-1, we conclude that the regulation of IL-8 mRNA by IL-1 is mediated via protein kinase-dependent signal transduction pathways. Our accumulated results have demonstrated that glucocorticoid suppression of IL-1-induced IL-8 mRNA occurs at the levels of post-transcription (mRNA stability) and protein synthesis.

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