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Imbalanced gp130-dependent signaling in macrophages alters macrophage colony-stimulating factor responsiveness via regulation of c-fms expression


Jenkins, BJ; Grail, D; Inglese, M; Quilici, C; Bozinovski, S; Wong, P; Ernst, M
2004-02
MOLECULAR AND CELLULAR BIOLOGY
Journal Article
24
4
1453-1463
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(DeltaSTAT/DeltaSTAT)) or extracellular signal-regulated kinases 1 and 2 (ERK1/2) mitogen-activated protein (MAP) kinase (gp130(Y757/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(DeltaSTAT/DeltaSTAT) mice, inhibition of macrophage colony formation was enhanced in gp130(Y757F/Y757F) Mice. in gp130(DeltaSTAT/DeltaSTAT) bone marrow-derived macrophages (BMMs), both IL-6- and M-CSF-induced ERK1/2 tyrosine phosphoryllation 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(DeltaSTAT/DeltaSTAT) 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.
AMER SOC MICROBIOLOGY
HEMATOPOIETIC PROGENITOR CELLS; LEUKEMIA INHIBITORY FACTOR; FACTOR-I; INDEPENDENT PATHWAYS; DENDRITIC CELLS; FACTOR RECEPTOR; CSF-1 RECEPTOR; GP130; INTERLEUKIN-6; ACTIVATION
10.1128/MCB.24.4.1453-1463.2004
Refer to copyright notice on published article.

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Creation Date 2004-02-01 12:00:00