Eosinophil major basic protein: First identified natural heparanase-inhibiting protein

Vladislav Temkin, Helena Aingorn, Ilaria Puxeddu, Orit Goldshmidt, Eyal Zcharia, Gerald J. Gleich, Israel Vlodavsky, Francesca Levi-Schaffer*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

59 Scopus citations

Abstract

Background: Heparanase and eosinophils are involved in several diseases, including inflammation, cancer, and angiogenesis. Objective: We sought to determine whether eosinophils produce active heparanase. Methods: Human peripheral blood eosinophils were isolated by immunoselection and tested for heparanase protein (immunocytochemistry, Western blot), mRNA (RT-PCR) and activity (Na2[35S]O4-labeled extracellular matrix degradation) before and after activation. Heparanase intracellular localization (confocal laser microscopy) and ability to bind to eosinophil major basic protein (MBP) were also evaluated (immunoprecipitation). A model of allergic peritonitis resulting in eosinophilia was induced in TNF knockout and wild-type mice for in vivo studies. Results: Eosinophils synthesized heparanase mRNA and contained heparanase in the active (50-kd) and latent (65-kd) forms. Heparanase partially co-localized with and was bound to MBP. No heparanase enzymatic activity was detected in eosinophils resting or activated with various agonists, including GM-CSF/C5a. Eosinophil lysates and MBP inhibited recombinant heparanase activity in a concentration-dependent manner (100%, 2 × 10-7 mol/L). Eosinophil peroxidase and eosinophil cationic protein, but not myelin basic protein or compound 48/ 80, partially inhibited heparanase activity. Poly-L-arginine at very high concentrations caused an almost complete inhibition. In allergic peritonitis, heparanase activity in the peritoneal fluid inversely correlated with eosinophil number. Conclusions: MBP is the first identified natural heparanase-inhibiting protein. Its presence in the eosinophil granules might indicate a protective function of these cells in diseases associated with inflammation and cancer progression.

Original languageAmerican English
Pages (from-to)703-709
Number of pages7
JournalJournal of Allergy and Clinical Immunology
Volume113
Issue number4
DOIs
StatePublished - Apr 2004

Bibliographical note

Funding Information:
Supported by a grant from the Aimwell Charitable Trust (FLS) and grants from the Center for the Study of Emerging Diseases (CSED) and the Israel Science Foundation (I.V.). F.L.S. is affiliated with the David R. Bloom Center of Pharmacy at The Hebrew University of Jerusalem.

Keywords

  • Allergic peritonitis
  • Angiogenesis
  • Eosinophils
  • Fibrosis
  • Heparanase
  • Inflammation
  • Major basic protein
  • Metastasis

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