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Culture of Macrophage Colony-stimulating Factor Differentiated Human Monocyte-derived Macrophages
06:46

Culture of Macrophage Colony-stimulating Factor Differentiated Human Monocyte-derived Macrophages

Published on: June 30, 2016

Imbalanced gp130-dependent signaling in macrophages alters macrophage colony-stimulating factor responsiveness via

Brendan J Jenkins1, Dianne Grail, Melissa Inglese

  • 1Ludwig Institute for Cancer Research, Colon Molecular and Cell Biology Laboratory, Parkville, Victoria, Australia. Brendan.Jenkins@ludwig.edu.au

Molecular and Cellular Biology
|January 30, 2004
PubMed

Insights

Interleukin-6 (IL-6) family cytokines inhibit macrophage development by regulating gp130-dependent ERK MAP kinase signaling. This pathway impacts c-fms gene activation, influencing monocyte/macrophage formation and proliferation.

Area of Science:

  • Immunology
  • Cell Biology
  • Molecular Biology

Background:

  • Interleukin-6 (IL-6) family cytokines signal through the common receptor subunit gp130.
  • The precise mechanisms by which these cytokines influence monocyte/macrophage development are not fully understood.
  • STAT1/3 and ERK1/2 pathways are downstream signaling components of gp130.

Purpose of the Study:

  • To elucidate the distinct roles of gp130-dependent STAT1/3 and ERK1/2 signaling in macrophage development.
  • To investigate the impact of these pathways on macrophage colony-stimulating factor (M-CSF)-induced proliferation and c-fms expression.
  • To establish a functional link between gp130 signaling and M-CSF-mediated macrophage formation.

Main Methods:

  • Utilized genetically modified macrophages lacking STAT1/3 (gp130(Delta STAT/Delta STAT)) or ERK1/2 activation (gp130(Y757F/Y757F)).
  • Assessed M-CSF-induced proliferation and colony formation in bone marrow-derived macrophages (BMMs).
  • Analyzed tyrosine phosphorylation of ERK1/2 and expression levels of c-fms in gp130 mutant BMMs.

Main Results:

  • IL-6 inhibition of M-CSF-induced colony formation was abolished in gp130(Delta STAT/Delta STAT) BMMs but enhanced in gp130(Y757F/Y757F) BMMs.
  • ERK1/2 phosphorylation was increased by IL-6 and M-CSF in gp130(Delta STAT/Delta STAT) BMMs, but reduced by M-CSF in gp130(Y757F/Y757F) BMMs.
  • c-fms expression was elevated in gp130(Delta STAT/Delta STAT) BMMs and reduced in gp130(Y757F/Y757F) BMMs, correlating with proliferation responses.

Conclusions:

  • gp130-dependent ERK MAP kinase signaling causally regulates c-fms gene activation.
  • This signaling pathway is critical for the inhibition of M-CSF-dependent macrophage development by IL-6 family cytokines.
  • Findings provide a molecular mechanism for cytokine-mediated control of monocyte/macrophage differentiation.

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