The JNK are important for development and survival of macrophages

S Roy Himes, David P Sester, Timothy Ravasi, Stephen L Cronau, Tedjo Sasmono, David A Hume

Research output: Contribution to journalArticlepeer-review

Abstract

We report in this study that activation of the JNK by the growth factor, CSF-1 is critical for macrophage development, proliferation, and survival. Inhibition of JNK with two distinct classes of inhibitors, the pharmacological agent SP600125, or the peptide D-JNKI1 resulted in cell cycle inhibition with an arrest at the G(2)/M transition and subsequent apoptosis. JNK inhibition resulted in decreased expression of CSF-1R (c-fms) and Bcl-x(L) mRNA in mature macrophages and repressed CSF-1-dependent differentiation of bone marrow cells to macrophages. Macrophage sensitivity to JNK inhibitors may be linked to phosphorylation of the PU.1 transcription factor. Inhibition of JNK disrupted PU.1 binding to an element in the c-fms gene promoter and decreased promoter activity. Promoter activity could be restored by overexpression of PU.1. A comparison of expression profiles of macrophages with 22 other tissue types showed that genes that signal JNK activation downstream of tyrosine kinase receptors, such as focal adhesion kinase, Nck-interacting kinase, and Rac1 and scaffold proteins are highly expressed in macrophages relative to other tissues. This pattern of expression may underlie the novel role of JNK in macrophages.
Original languageEnglish
Pages (from-to)2219-28
Number of pages10
JournalJournal of Immunology
Volume176
Issue number4
Publication statusPublished - 15 Feb 2006

Keywords

  • Animals
  • Bone Marrow Cells
  • Cell Differentiation
  • Cell Survival
  • Cells, Cultured
  • DNA
  • Gene Expression Profiling
  • Gene Expression Regulation
  • JNK Mitogen-Activated Protein Kinases
  • Macrophage Colony-Stimulating Factor
  • Macrophages
  • Mice
  • Oligonucleotide Array Sequence Analysis
  • Phosphorylation
  • Promoter Regions, Genetic
  • Protein Binding
  • Proto-Oncogene Proteins
  • RNA, Messenger
  • Receptor, Macrophage Colony-Stimulating Factor
  • Signal Transduction
  • Trans-Activators

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