CSF-1 (M-CSF) enhances the inflammatory response of fibronectin-primed macrophages: Pathways involved in activation of the cytokine network

Sergey G. Kremlev, Andrei I. Chapoval, Robert Evans

Research output: Contribution to journalArticlepeer-review

6 Scopus citations

Abstract

We have previously reported that the priming of thioglycollate-elicited peritoneal macrophages (PMφ), as a representative population of mono-nuclear phagocytes (MNP), by macrophage-colony-stimulating factor (M-CSF or CSF- 1) rendered these cells more susceptible to secondary stimulation by extracellular matrix (ECM) proteins, in particular fibronectin (FN), and that at least two β1 integrins, VLA 4 (α4β1 or CD49d) and VLA 5 (α5β1 or CD49e), regulate IL-6 gene expression when PMφ come into contact with FN. In this report, we focused our attention on resident PMφ, as a more mature/differentiated MNP subpopulation. By using granulocyte-macrophage colony-stimulating factor (GM-CSF)- and IL-6-knockout (null) mice, we demonstrated that the cooperative effect between CSF-1 and FN in IL-6 release was a result of a sequential stimulation of the GM-CSF, but not the TNF-α, gene via interaction with VLA 5. We also showed that regardless of the presence or absence of CSF-1 or FN, IL-6 inhibits GM-CSF and TNF-α gene expression in an autocrine manner. The observed effects were specific because CSF-1 enhanced VLA 5 expression and blocking FN-treated resident PMφ in vitro with VLA 5 monoclonal antibodies inhibited the IL-6 response. We found that treatment of resident PMφ with the protein kinase C inhibitor, staurosporine, and the activator, phorbol myristate acetate (PMA), resulted in marked modulation of either FN- or FN/CSF-1-induced cytokine release. An increased level of VLA 5 expression was observed in PMA-treated resident PMφ. We concluded that in inflammatory processes, CSF-1 drives a number of pathways involved in the regulation of the expression of several genes and renders MNP highly susceptible to stimulation by ECM proteins that transform the MNP into secretory inflammatory cells.

Original languageEnglish (US)
Pages (from-to)228-243
Number of pages16
JournalNatural Immunity
Volume16
Issue number5-6
DOIs
StatePublished - 1998
Externally publishedYes

Keywords

  • Cytokines
  • Extracellular matrix
  • Inflammation
  • Monocytes/macrophages
  • Transgenic/knockout

ASJC Scopus subject areas

  • Immunology

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