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Molecular and Cellular Biology, February 2004, p. 1453-1463, Vol. 24, No. 4
0270-7306/04/$08.00+0     DOI: 10.1128/MCB.24.4.1453-1463.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

Imbalanced gp130-Dependent Signaling in Macrophages Alters Macrophage Colony-Stimulating Factor Responsiveness via Regulation of c-fms Expression

Ludwig Institute for Cancer Research, Colon Molecular and Cell Biology Laboratory,¹ The Walter and Eliza Hall Institute for Medical Research,³ Pharmacology Department, University of Melbourne, Parkville, Victoria, Australia²

Received 21 May 2003/ Returned for modification 30 July 2003/ Accepted 7 November 2003

The mechanisms by which interleukin-6 (IL-6) family cytokines, which utilize the common receptor signaling subunit gp130, influence monocyte/macrophage development remain unclear. Here we have utilized macrophages devoid of either gp130-dependent STAT1/3 (gp130^STAT/STAT) or extracellular signal-regulated kinases 1 and 2 (ERK1/2) mitogen-activated protein (MAP) kinase (gp130^Y757F/Y757F) activation to assess the individual contribution of each pathway to macrophage formation. While the inhibition by IL-6 of macrophage colony-stimulating factor (M-CSF)-induced colony formation observed in gp130^wt/wt mice was abolished in gp130^STAT/STAT mice, inhibition of macrophage colony formation was enhanced in gp130^Y757F/Y757F mice. In gp130^STAT/STAT bone marrow-derived macrophages (BMMs), both IL-6- and M-CSF-induced ERK1/2 tyrosine phosphorylation was enhanced. By contrast, tyrosine phosphorylation of ERK1/2 in response to M-CSF was reduced in gp130^Y757F/Y757F BMMs, and the pattern of ERK1/2 activation in gp130 mutant BMMs correlated with their opposing responsiveness to M-CSF-induced proliferation. When compared to the level of expression in gp130^wt/wt BMMs, c-fms expression was elevated in gp130^STAT/STAT BMMs but reduced in gp130^Y757F/Y757F BMMs. Finally, an ERK1/2 inhibitor suppressed M-CSF-induced BMM proliferation, and this result corresponded to a reduction in c-fms expression. Collectively, these results provide a functional and causal correlation between gp130-dependent ERK MAP kinase signaling and c-fms gene activation, a finding that provides a potential mechanism underlying the inhibition of M-CSF-dependent macrophage development by IL-6 family cytokines in mice.

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