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IL-6 mediated activation of STAT3 bypasses Janus kinases in terminally differentiated B lineage cells

Yevgeny Kopantzev1, Mary Heller, Nalini Swaminathan

  • 1Laboratory of Cellular and Molecular Biology, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, MD 20892, USA.

Oncogene
|October 3, 2002
PubMed

Insights

Interleukin-6 (IL-6) signaling in B cells typically requires Janus kinases (Jaks), but this study found STAT3 phosphorylation occurs without Jak1. The MAPK pathway, not Jaks, appears critical for IL-6 mediated STAT3 activation in plasma cells.

Area of Science:

  • Immunology
  • Cellular Signaling
  • Molecular Biology

Background:

  • Cytokine signaling often involves receptor-associated Janus kinases (Jaks) activating Signal Transducer and Activator of Transcription (STAT) factors.
  • Interleukin-6 (IL-6) signaling in B cells was thought to require Jak1, Jak2, and Tyk2 for STAT3 activation.
  • Jak1 is considered essential for IL-6 mediated STAT3 activation in many cell types.

Purpose of the Study:

  • To investigate the role of Janus kinases (Jaks) in Interleukin-6 (IL-6) mediated STAT3 phosphorylation in B lineage cells.
  • To identify alternative signaling pathways involved in IL-6 induced STAT3 activation.
  • To re-evaluate the necessity of Jaks in cytokine signaling cascades.

Main Methods:

  • Utilized end-stage B cell (plasma cell) lines lacking Jak1 expression.
  • Assessed STAT3 phosphorylation in response to IL-6 stimulation.
  • Employed MEK, PI-3K, and Src kinase inhibitors to probe signaling pathways.
  • Analyzed Jak1 phosphorylation status in response to IL-6 and MEK inhibition.

Main Results:

  • Plasma cell lines lacking Jak1 expression still exhibited IL-6-mediated STAT3 tyrosine phosphorylation.
  • No requirement for other Jak family members was observed in STAT3 activation.
  • STAT3 phosphorylation was dose-dependently inhibited by the MEK inhibitor U0126.
  • STAT3 phosphorylation was unaffected by PI-3K or Src kinase inhibitors.
  • In Jak1-expressing cells, IL-6 induced Jak1 phosphorylation, which was not inhibited by U0126.

Conclusions:

  • The MAPK pathway plays a critical role in IL-6 mediated STAT3 tyrosine phosphorylation.
  • Jak kinases may not be required for IL-6 induced STAT3 activation in these B cell lines.
  • These findings suggest a need to re-evaluate the role of Jaks in other cytokine signaling pathways.

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