Signal transduction pathways induced by GM-CSF in microglia: significance in the control of proliferation

Glia. 1999 Jun;26(4):344-52. doi: 10.1002/(sici)1098-1136(199906)26:4<344::aid-glia8>3.0.co;2-l.

Abstract

Communication between cells of the central nervous system (CNS) and of the immune system is accomplished by a network of cytokines and growth factors. Certain cytokines and growth factors cause activation of microglia, contributing to inflammatory states in the CNS. Granulocyte-macrophage colony-stimulating factor (GM-CSF) has numerous effects on microglia, ranging from induction of proliferation to changes in morphology. GM-CSF is also a growth factor for cells of the myeloid lineage, and the signal tranduction induced by GM-CSF in these cells has been extensively studied. Most notably, the importance of the Jak/STAT and MAP kinase pathways in mitogenesis has been shown in many different systems. We show here that primary microglia and a microglia cell line, BV-2, have a Jak/STAT expression pattern and GM-CSF inducibility similar to that of monocytes and macrophages. Primary microglia and BV-2 cells expressed identical Jak/STATs: Jakl, Jak2, Jak3, Tyk2, STAT1alpha/beta, STAT3, STAT5A, STAT5B, and STAT6. In addition, GM-CSF induced Jak2, STAT5A, and STAT5B in BV-2 cells, as it does in monocytes and macrophages. Immunocytochemical analysis showed that STAT5 translocates to the nucleus following GM-CSF stimulation of microglia. We also found the MAP kinases, ERK1 and ERK2, to be phosphorylated in microglia and BV-2 cells following induction by GM-CSF. Jak2, STAT5A, STAT5B, and ERKs are known to be important in controlling cellular proliferation. Drugs that block these pathways may become tools to control inflammation in the CNS by limiting microglial proliferation.

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Calcium-Calmodulin-Dependent Protein Kinases / metabolism
  • Cell Division
  • Cell Line
  • Cell Nucleus / metabolism
  • Cells, Cultured
  • DNA-Binding Proteins / biosynthesis
  • Granulocyte-Macrophage Colony-Stimulating Factor / metabolism*
  • Granulocyte-Macrophage Colony-Stimulating Factor / pharmacology
  • Interferon-Stimulated Gene Factor 3
  • Janus Kinase 1
  • Janus Kinase 2
  • Janus Kinase 3
  • Microglia / cytology
  • Microglia / drug effects
  • Microglia / metabolism*
  • Milk Proteins*
  • Mitogen-Activated Protein Kinase 1
  • Mitogen-Activated Protein Kinase 3
  • Mitogen-Activated Protein Kinases*
  • Protein Biosynthesis
  • Protein-Tyrosine Kinases / biosynthesis
  • Proto-Oncogene Proteins*
  • Rats
  • Rats, Wistar
  • STAT3 Transcription Factor
  • STAT5 Transcription Factor
  • STAT6 Transcription Factor
  • Signal Transduction*
  • TYK2 Kinase
  • Trans-Activators / biosynthesis
  • Transcription Factors / biosynthesis

Substances

  • DNA-Binding Proteins
  • Interferon-Stimulated Gene Factor 3
  • Jak3 protein, rat
  • Milk Proteins
  • Proto-Oncogene Proteins
  • STAT3 Transcription Factor
  • STAT5 Transcription Factor
  • STAT6 Transcription Factor
  • Stat3 protein, rat
  • Stat5a protein, rat
  • Stat5b protein, rat
  • Trans-Activators
  • Transcription Factors
  • gamma interferon activation factor
  • Granulocyte-Macrophage Colony-Stimulating Factor
  • Protein-Tyrosine Kinases
  • Jak1 protein, rat
  • Jak2 protein, rat
  • Janus Kinase 1
  • Janus Kinase 2
  • Janus Kinase 3
  • TYK2 Kinase
  • Tyk2 protein, rat
  • Calcium-Calmodulin-Dependent Protein Kinases
  • Mitogen-Activated Protein Kinase 1
  • Mitogen-Activated Protein Kinase 3
  • Mitogen-Activated Protein Kinases