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Inhibition of p38alpha MAPK disrupts the pathological loop of proinflammatory factor production in the

Tony Navas1, Li Zhou, Myka Estes

  • 1Scios Inc, Fremont, CA, USA.

Leukemia & Lymphoma
|October 25, 2008
PubMed

Insights

In myelodysplastic syndromes (MDS), p38 MAPK inhibition reduces inflammatory cytokines like TNFalpha and IL-1beta, protecting hematopoietic stem cells from apoptosis and supporting p38alpha as a therapeutic target.

Area of Science:

  • Hematology
  • Molecular Biology
  • Immunology

Background:

  • Myelodysplastic syndromes (MDS) cause ineffective hematopoiesis and cytopenias, particularly in the elderly.
  • Overactivated p38 MAPK in MDS hematopoietic progenitors contributes to apoptosis and hematopoietic suppression.
  • Myelosuppressive and proinflammatory cytokines are implicated in MDS pathogenesis.

Purpose of the Study:

  • To investigate the role of p38 MAPK in cytokine secretion within the MDS bone marrow microenvironment.
  • To evaluate the therapeutic potential of the p38alpha inhibitor SCIO-469 in MDS.

Main Methods:

  • Demonstrated p38 MAPK-dependent secretion of TNFalpha and IL-1beta by bone marrow cells.
  • Utilized an in vitro inflammation-simulated bone marrow microenvironment model.
  • Assessed the effect of SCIO-469 on cytokine secretion and progenitor cell apoptosis ex vivo.

Main Results:

  • p38 MAPK inhibition reduced TNFalpha and IL-1beta secretion in a p38 MAPK-dependent manner.
  • SCIO-469 treatment inhibited TNF secretion and protected normal progenitors from apoptosis.
  • p38 inhibition diminished the expression of inflammatory chemokines induced by TNFalpha or IL-1beta.

Conclusions:

  • p38 MAPK inhibition exhibits anti-inflammatory effects on the bone marrow microenvironment in MDS.
  • p38 inhibition provides cytoprotective effects on progenitor survival.
  • These findings support p38alpha as a potential therapeutic target for MDS and related inflammatory bone marrow failure diseases.

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