Cross-talk between ICAM-1 and granulocyte-macrophage colony-stimulating factor receptor signaling modulates eosinophil survival and activation

J Immunol. 2008 Mar 15;180(6):4182-90. doi: 10.4049/jimmunol.180.6.4182.

Abstract

Reversal of eosinophilic inflammation has been an elusive therapeutic goal in the management of asthma pathogenesis. In this regard, GM-CSF is a primary candidate cytokine regulating eosinophil activation and survival in the lung; however, its molecular mechanism of propagation and maintenance of stimulated eosinophil activation is not well understood. In this study, we elucidate those late interactions occurring between the GM-CSF receptor and activated eosinophil signaling molecules. Using coimmunoprecipitation with GM-CSF-stimulated eosinophils, we have identified that the GM-CSF receptor beta-chain (GMRbeta) interacted with ICAM-1 and Shp2 phosphatase, as well as Slp76 and ADAP adaptor proteins. Separate experiments using affinity binding with a tyrosine-phosphorylated peptide containing an ITIM (ICAM-1 residues 480-488) showed binding to Shp2 phosphatase and GMRbeta. However, the interaction of GMRbeta with the phosphorylated ICAM-1-derived peptide was observed only with stimulated eosinophil lysates, suggesting that the interaction of GMRbeta with ICAM-1 required phosphorylated Shp2 and/or phosphorylated GMRbeta. Importantly, we found that inhibition of ICAM-1 in activated eosinophils blocked GM-CSF-induced expression of c-fos, c-myc, IL-8, and TNF-alpha. Moreover, inhibition of ICAM-1 expression with either antisense oligonucleotide or an ICAM-1-blocking Ab effectively inhibited ERK activation and eosinophil survival. We concluded that the interaction between ICAM-1 and the GM-CSF receptor was essential for GM-CSF-induced eosinophil activation and survival. Taken together, these results provide novel mechanistic insights defining the interaction between ICAM-1 and the GM-CSF receptor and highlight the importance of targeting ICAM-1 and GM-CSF/IL-5/IL-3 receptor systems as a therapeutic strategy to counter eosinophilia in asthma.

Publication types

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

MeSH terms

  • Cell Survival / immunology
  • Cells, Cultured
  • Cytokine Receptor Common beta Subunit / metabolism*
  • Cytokine Receptor Common beta Subunit / physiology
  • Eosinophils / cytology*
  • Eosinophils / enzymology
  • Eosinophils / metabolism*
  • Granulocyte-Macrophage Colony-Stimulating Factor / metabolism
  • Granulocyte-Macrophage Colony-Stimulating Factor / physiology
  • Humans
  • Intercellular Adhesion Molecule-1 / metabolism*
  • Intercellular Adhesion Molecule-1 / physiology
  • Peptides / metabolism
  • Peptides / physiology
  • Protein Binding / immunology
  • Protein Subunits / metabolism
  • Protein Subunits / physiology
  • Protein Tyrosine Phosphatase, Non-Receptor Type 11 / metabolism
  • Protein Tyrosine Phosphatase, Non-Receptor Type 11 / physiology
  • Receptor Cross-Talk* / immunology
  • Receptors, Granulocyte-Macrophage Colony-Stimulating Factor / metabolism*
  • Receptors, Granulocyte-Macrophage Colony-Stimulating Factor / physiology
  • Signal Transduction* / immunology

Substances

  • Cytokine Receptor Common beta Subunit
  • Peptides
  • Protein Subunits
  • Receptors, Granulocyte-Macrophage Colony-Stimulating Factor
  • Intercellular Adhesion Molecule-1
  • Granulocyte-Macrophage Colony-Stimulating Factor
  • Protein Tyrosine Phosphatase, Non-Receptor Type 11