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IL6 inhibition of inflammatory S100A8/9 proteins is NF-κB mediated in essential thrombocythemia

Miloš Diklić1, Olivera Mitrović-Ajtić1, Tijana Subotički1

  • 1Department of Molecular Oncology, Institute for Medical Research, University of Belgrade, Belgade, Serbia.

Cell Biochemistry and Function
|December 31, 2019
PubMed

Insights

Inflammation reduces myeloid S100A8/9 proteins in essential thrombocythemia (ET) via negative feedback. S100A8/9 may serve as a diagnostic marker for inflammation in myeloproliferative neoplasms (MPN).

Area of Science:

  • * Molecular biology
  • * Immunology
  • * Hematology

Background:

  • * Myeloproliferative neoplasms (MPN) are characterized by abnormal myeloid cell proliferation.
  • * S100A proteins (S100A8/9) are implicated in inflammatory processes.
  • * The role of inflammatory cytokines in S100A protein regulation in MPN is not fully understood.

Purpose of the Study:

  • * To elucidate the mechanism of myeloid-related S100A protein activation by inflammatory cytokines in MPN.
  • * To investigate the signaling pathways (NF-κB, PI3K-AKT, JAK-STAT) involved in S100A protein induction.
  • * To assess the potential of S100A8/9 as a diagnostic marker for inflammation in MPN.

Main Methods:

  • * Microarray analysis of MPN-derived CD34+ cells.
  • * Immunoblotting and flow cytometry to analyze signaling pathways and protein levels.
  • * Assessment of S100A8/9 expression in granulocytes and correlation with JAK2V617F allele burden.

Main Results:

  • * Reduced gene expression related to NF-κB and inflammation signaling in MPN-derived CD34+ cells.
  • * IL6 and IL10 decreased S100A8/9 protein levels via NF-κB and PI3K signaling in essential thrombocythemia (ET) mononuclear cells.
  • * Increased S100A8/9 positive granulocytes in ET and primary myelofibrosis, correlated with JAK2V617F allele burden.
  • * S100A8/9 heterodimer induced JAK1/2-dependent mitotic arrest in ET-derived granulocytes.

Conclusions:

  • * Inflammation negatively regulates myeloid S100A8/9 proteins through a feedback mechanism in ET.
  • * S100A8/9 serves as a potential diagnostic marker for inflammation in MPN.
  • * Inhibition of NF-κB and JAK1/2 signaling is crucial for regulating myeloproliferation and MPN therapy.
Keywords:
G2/M phaseNF-κB signallingS100A8/9interleukin 10interleukin 6myeloproliferative neoplasm

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