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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

Brendan J. Jenkins,1* Dianne Grail,1 Melissa Inglese,1 Cathy Quilici,1 Steven Bozinovski,2 Peter Wong,3 and Matthias Ernst1

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{Delta}STAT/{Delta}STAT) or extracellular signal-regulated kinases 1 and 2 (ERK1/2) mitogen-activated protein (MAP) kinase (gp130Y757F/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 gp130wt/wt mice was abolished in gp130{Delta}STAT/{Delta}STAT mice, inhibition of macrophage colony formation was enhanced in gp130Y757F/Y757F mice. In gp130{Delta}STAT/{Delta}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 gp130Y757F/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 gp130wt/wt BMMs, c-fms expression was elevated in gp130{Delta}STAT/{Delta}STAT BMMs but reduced in gp130Y757F/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.

* Corresponding author. Mailing address: Ludwig Institute for Cancer Research, Colon Molecular and Cell Biology Laboratory, P. O. Box 2008, Royal Melbourne Hospital, Victoria 3050, Australia. Phone: 61 3 9341 3155. Fax: 61 3 9341 3104. E-mail: Brendan.Jenkins{at}ludwig.edu.au.

Molecular and Cellular Biology, February 2004, p. 1453-1463, Vol. 24, No. 4
0022-538X/04/$08.00+0     DOI: 10.1128/MCB.24.4.1453-1463.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.



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