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Proteolysis of macrophage inflammatory protein-1alpha isoforms LD78beta and LD78alpha by neutrophil-derived serine

Ok Hee Ryu1, Sun Jin Choi, Erhan Firatli

  • 1Human Craniofacial Genetics Section, NIDCR, National Institutes of Health, Bethesda, Maryland 20892, USA.

The Journal of Biological Chemistry
|February 25, 2005
PubMed

Insights

Neutrophil proteases like cathepsin G, elastase, and proteinase 3 degrade macrophage inflammatory protein-1alpha (MIP-1alpha), reducing its activity. This degradation is impaired in Papillon-Lefevre syndrome, potentially causing tissue damage.

Area of Science:

  • Immunology
  • Protease biochemistry
  • Molecular biology

Background:

  • Macrophage inflammatory protein-1alpha (MIP-1alpha) recruits leukocytes to infection sites, but excess can cause tissue damage.
  • Neutrophil serine proteases can modulate chemokine activity through proteolytic cleavage.
  • Understanding MIP-1alpha proteolysis is crucial for controlling inflammatory responses.

Purpose of the Study:

  • To investigate the in vitro proteolysis of MIP-1alpha isoforms by neutrophil-derived serine proteases.
  • To identify specific cleavage sites and compare the activities of intact and degraded MIP-1alpha.
  • To assess the role of MIP-1alpha degradation in Papillon-Lefevre syndrome.

Main Methods:

  • Recombinant human MIP-1alpha isoforms (LD78beta and LD78alpha) were expressed and purified.
  • Protease cleavage sites were analyzed using mass spectrometry and peptide sequencing.
  • Chemotactic activities were compared before and after proteolysis; experiments included neutrophil lysates from healthy individuals and Papillon-Lefevre syndrome patients.

Main Results:

  • MIP-1alpha isoforms LD78beta and LD78alpha were cleaved by neutrophil lysates at specific sites (Thr16-Ser17, Phe24-Ile25, Tyr28-Phe29, Thr31-Ser32).
  • Cathepsin G preferentially cleaved at Phe24-Ile25 and Tyr28-Phe29, while elastase and proteinase 3 cleaved at Thr16-Ser17 and Thr31-Ser32.
  • Proteolysis of LD78beta led to a loss of chemotactic activity; degradation was impaired in Papillon-Lefevre syndrome neutrophil lysates.

Conclusions:

  • Neutrophil serine proteases effectively degrade MIP-1alpha, reducing its inflammatory activity.
  • Impaired MIP-1alpha degradation in Papillon-Lefevre syndrome may contribute to periodontal tissue destruction.
  • Dysregulation of MIP-1alpha proteolysis is implicated in the inflammatory response within the periodontium.

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