Evaluation of the effect of human beta-defensins on neutrophil apoptosis

Int Immunol. 2008 Apr;20(4):543-53. doi: 10.1093/intimm/dxn012. Epub 2008 Feb 27.

Abstract

Peptide antibiotics possess the potent antimicrobial activities against invading microorganisms and contribute to the innate host defense. Antimicrobial human beta-defensins (hBDs) not only exhibit potent bactericidal activities against Gram-negative and Gram-positive bacteria but also function as immunomodulatory molecules by inducing cytokine and chemokine production and inflammatory and immune cell activation. Neutrophil is a critical effector cell in host defense against microbial infection, and its lifespan is regulated by various pathogen- and host-derived substances. Here, to further evaluate the role of hBDs in innate immunity, we investigated the action of hBD-1 to -4 on neutrophil apoptosis. Neutrophil apoptosis was assessed using human blood neutrophils based on the morphological changes. Of note, hBD-3 most potently suppressed neutrophil apoptosis among hBD-1 to -4, accompanied with the down-regulation of truncated Bid (a pro-apoptotic protein), up-regulation of Bcl-x(L) (an anti-apoptotic protein) and inhibition of mitochondrial membrane potential change and caspase 3 activity. Furthermore, we revealed that neutrophils expressed CC chemokine receptor (CCR) 6, and the action of hBD-3 was completely abrogated by a neutralizing anti-CCR6 mAb. Collectively, these observations suggest that hBDs, especially hBD-3, can not only kill bacteria but also modulate (suppress) neutrophil apoptosis via the action on CCR6. Suppression of neutrophil apoptosis results in the prolongation of their lifespan and may be advantageous for the host defense against bacterial invasion.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antibodies, Monoclonal / metabolism
  • Antigen-Antibody Reactions
  • Apoptosis / drug effects*
  • Apoptosis / immunology
  • BH3 Interacting Domain Death Agonist Protein / biosynthesis
  • BH3 Interacting Domain Death Agonist Protein / drug effects
  • BH3 Interacting Domain Death Agonist Protein / immunology
  • Calcium / metabolism
  • Caspase 3 / drug effects
  • Caspase 3 / metabolism
  • Cytokines / biosynthesis
  • Cytokines / drug effects
  • Enzyme Activation / drug effects
  • Enzyme Activation / immunology
  • Humans
  • Leukocytes, Mononuclear / cytology
  • Leukocytes, Mononuclear / drug effects
  • Leukocytes, Mononuclear / immunology
  • Mitochondrial Membranes / drug effects
  • Mitochondrial Membranes / metabolism
  • Neutrophils / cytology
  • Neutrophils / drug effects*
  • Neutrophils / immunology
  • Receptors, CCR6 / metabolism
  • bcl-X Protein / biosynthesis
  • bcl-X Protein / drug effects
  • bcl-X Protein / immunology
  • beta-Defensins / pharmacology*

Substances

  • Antibodies, Monoclonal
  • BH3 Interacting Domain Death Agonist Protein
  • BID protein, human
  • CCR6 protein, human
  • Cytokines
  • Receptors, CCR6
  • bcl-X Protein
  • beta-Defensins
  • Caspase 3
  • Calcium