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Role of NFκB in the regulation of macrophage colony stimulating factor by tumor necrosis factor‐α in ST2 bone stromal cells
Author(s) -
Isaacs S.D.,
Fan X.,
Fan D.,
Gewant H.,
Murphy T.C.,
Farmer P.,
Taylor W.R.,
Nanes M.S.,
Rubin J.
Publication year - 1999
Publication title -
journal of cellular physiology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.529
H-Index - 174
eISSN - 1097-4652
pISSN - 0021-9541
DOI - 10.1002/(sici)1097-4652(199905)179:2<193::aid-jcp9>3.0.co;2-3
Subject(s) - stromal cell , tumor necrosis factor alpha , macrophage , macrophage colony stimulating factor , tumor necrosis factor α , cancer research , nf κb , microbiology and biotechnology , biology , immunology , signal transduction , biochemistry , in vitro
Abstract Expression of MCSF in bone is important to the regulation of osteoclastogenesis. We show here that tumor necrosis factor‐α (TNFα) increases the production of both soluble (sMCSF) and membrane‐bound (mMCSF) macrophage colony stimulating factor by ST2 bone stromal cells. Treatment of ST2 cells with TNFα caused sMCSF levels to increase by 394 ± 5% from basal; mMCSF rose by 316 ± 66% from 30 ± 10 per 100,000 cells in the same time. These increases were consistent with increased expression of mRNAs encoding both isoforms. Increases in MCSF mRNA are also seen after stimulation with dexamethasone. To investigate the potential role of NFκB in this TNFα effect, we treated cells with sodium salicylate (NaS), an inhibitor of NFκB translocation. NaS decreased TNFα‐stimulated NFκB activation by 50% as assessed by EMSA. Despite inhibition of NFκB signaling, NaS enhanced TNFα‐stimulated MCSF secretion and did not prevent TNFα‐stimulated increases in sMCSF mRNA, suggesting that NFκB was not involved in TNFα effect on the gene. TNFα failed to stimulate transcription of a 774 nucleotide MCSF promoter‐luciferase reporter transfected into ST2 cells which contained the NFκB consensus sequence. Deletion of the seven nucleotides containing the NFκB homology response sequence from the MCSF promoter increased basal gene transcription by twofold. TNFα thus contributes to an osteoclastogenic environment through upregulation of bone expression of both MCSF isoforms. Our data suggests that NFκB is not the major signaling pathway through which this occurs. J. Cell. Physiol. 179:193–200, 1999. © 1999 Wiley‐Liss, Inc.