Gp130 and ras mediated signaling in human plasma cell line INA-6: a cytokine-regulated tumor model for plasmacytoma

Hematol J. 2001;2(1):42-53. doi: 10.1038/sj.thj.6200075.

Abstract

Introduction: Cytokines of the gp130-family, particularly interleukin(IL)-6, play a crucial role in the propagation of malignant plasma cells.

Materials and methods: The role of IL-6 and other gp130-cytokines was studied in the human plasma cell line INA-6 in vitro and in INA-6 xenografts. The proliferative response to gp130-cytokines was evaluated and activated components of gp130-signaling pathways were identified by Western blotting and DNA binding studies. Specifically, expression of IL-6 and receptors for IL-6 and leukemia inhibitory factor were analysed by RT-PCR and ELISA.

Results: The plasma cell line INA-6 was cultured for several years remaining strictly dependent on exogenous IL-6. Other gp130-cytokines had no significant effect on INA-6 cell proliferation in vitro. Due to an activating mutation in the N-ras gene, mitogen-activated protein kinases (MAPK) were constitutively phosphorylated. In contrast, signal transducer and activator of transcription(STAT)-3 activation was dependent on stimulation with IL-6. Blocking of either one of these pathways resulted in a significant decrease of INA-6 cell proliferation. Remarkably, INA-6 xenografts did not require exogeneous IL-6 for proliferation in vivo. Instead, an autocrine IL-6 loop and, in certain tumor sublines, responsiveness to additional gp130-cytokines was induced during in vivo growth.

Conclusion: Activation of the gp130 signal transducer is mandatory for INA-6 cell growth in vitro and in vivo. Both the MAPK and the Jak/STAT pathway are operative in malignant plasma cells and either one is essential for plasma cell growth. The INA-6 cell line provides a preclinical model to study growth regulation of human plasmacytoma cells and to evaluate novel therapeutic strategies.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aged
  • Aged, 80 and over
  • Animals
  • Antigens, CD / physiology*
  • Cell Division / drug effects
  • Cell Division / physiology
  • Cytokine Receptor gp130
  • DNA-Binding Proteins / drug effects
  • DNA-Binding Proteins / metabolism
  • Female
  • Humans
  • Interleukin-6 / pharmacology
  • Male
  • Membrane Glycoproteins / physiology*
  • Mice
  • Mice, SCID
  • Mitogen-Activated Protein Kinases / metabolism
  • Neoplasms, Experimental
  • Plasmacytoma / pathology*
  • STAT1 Transcription Factor
  • STAT3 Transcription Factor
  • Signal Transduction
  • Trans-Activators / drug effects
  • Trans-Activators / metabolism
  • Transplantation, Heterologous
  • Tumor Cells, Cultured / cytology*
  • Tumor Cells, Cultured / drug effects
  • Tumor Cells, Cultured / transplantation
  • ras Proteins / physiology*

Substances

  • Antigens, CD
  • DNA-Binding Proteins
  • IL6ST protein, human
  • Il6st protein, mouse
  • Interleukin-6
  • Membrane Glycoproteins
  • STAT1 Transcription Factor
  • STAT1 protein, human
  • STAT3 Transcription Factor
  • STAT3 protein, human
  • Stat1 protein, mouse
  • Stat3 protein, mouse
  • Trans-Activators
  • Cytokine Receptor gp130
  • Mitogen-Activated Protein Kinases
  • ras Proteins