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Mast cell dipeptidyl peptidase I mediates survival from sepsis

Jon Mallen-St Clair1, Christine T N Pham, S Armando Villalta

  • 1Department of Medicine and The Cardiovascular Research Institute, University of California, San Francisco, California 94143-0911, USA.

The Journal of Clinical Investigation
|February 18, 2004
PubMed

Insights

Mice lacking dipeptidyl peptidase I (DPPI) show increased survival from sepsis. This survival benefit is linked to mast cell DPPI and higher levels of interleukin-6 (IL-6), suggesting DPPI as a therapeutic target.

Area of Science:

  • Immunology
  • Molecular Biology
  • Pathology

Background:

  • Sepsis is a life-threatening condition with limited therapeutic options.
  • Dipeptidyl peptidase I (DPPI) activates proteases involved in host defense against bacterial infections.

Purpose of the Study:

  • To investigate the role of DPPI in sepsis pathogenesis.
  • To identify DPPI as a potential therapeutic target for sepsis treatment.

Main Methods:

  • Comparison of DPPI knockout (DPPI(-/-)) and wild-type (DPPI(+/+)) mice in a cecal ligation and puncture (CLP) sepsis model.
  • Assessment of survival rates and cytokine levels (IL-6) in peritoneal fluid and serum.
  • In vitro experiments demonstrating IL-6 cleavage by DPPI-activated peptidases.

Main Results:

  • DPPI(-/-) mice exhibited significantly higher survival rates following CLP compared to DPPI(+/+) mice.
  • The survival advantage in DPPI(-/-) mice was attributed to the absence of DPPI specifically in mast cells.
  • Septic DPPI(-/-) mice showed elevated levels of IL-6, and its deletion abolished the survival benefit.
  • DPPI-activated peptidases were shown to cleave IL-6 in vitro.

Conclusions:

  • Mast cell DPPI activity is detrimental to the host during sepsis.
  • Elevated IL-6 levels in DPPI-deficient mice contribute to sepsis survival.
  • DPPI represents a novel therapeutic target for sepsis treatment.

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