Activated protein C modulates the proinflammatory activity of dendritic cells

Abstract

Background

Previous studies have demonstrated the beneficial activity of activated protein C in allergic diseases including bronchial asthma and rhinitis. However, the exact mechanism of action of activated protein C in allergies is unclear. In this study, we hypothesized that pharmacological doses of activated protein C can modulate allergic inflammation by inhibiting dendritic cells.

Materials and methods

Dendritic cells were prepared using murine bone marrow progenitor cells and human peripheral monocytes. Bronchial asthma was induced in mice that received intratracheal instillation of ovalbumin-pulsed dendritic cells.

Results

Activated protein C significantly increased the differentiation of tolerogenic plasmacytoid dendritic cells and the secretion of type I interferons, but it significantly reduced lipopolysaccharide-mediated maturation and the secretion of inflammatory cytokines in myeloid dendritic cells. Activated protein C also inhibited maturation and the secretion of inflammatory cytokines in monocyte-derived dendritic cells. Activated protein C-treated dendritic cells were less effective when differentiating naïve CD4 T-cells from Th1 or Th2 cells, and the cellular effect of activated protein C was mediated by its receptors. Mice that received adoptive transfer of activated protein C-treated ovalbumin-pulsed dendritic cells had significantly less airway hyperresponsiveness, significantly decreased lung concentrations of Th1 and Th2 cytokines, and less plasma concentration of immunoglobulin E when compared to control mice.

Conclusion

These results suggest that dendritic cells mediate the immunosuppressive effect of activated protein C during allergic inflammation.

Keywords:

• allergy
• dendritic cells
• coagulation
• protein C pathway

Acknowledgments

This study was supported by a grant-in-aid (number 26860605) from the Ministry of Education, Culture, Sports, Science, and Technology of Japan. The funders had no role in the study design, data analysis, decision to publish, or preparation of the manuscript.

Disclosure

Etsuko Harada is an employee of the Iwade Research Institute of Mycology, and Takahiro Matsumoto is an employee of BONAC Corporation. The other authors report no conflicts of interest in this work.