Cytokine enhancement of complement-dependent phagocytosis by macrophages: synergy of tumor necrosis factor-alpha and granulocyte-macrophage colony-stimulating factor for phagocytosis of Cryptococcus neoformans

Eur J Immunol. 1992 Jun;22(6):1447-54. doi: 10.1002/eji.1830220617.

Abstract

We have examined the regulation of complement dependent phagocytosis by macrophage-activating cytokines. Tumor necrosis factor (TNF)-alpha and granulocyte-macrophage colony-stimulating factor (GM-CSF), but not interferon-gamma, interleukin-4 or macrophage-CSF, stimulated ingestion of the encapsulated fungal pathogen Cryptococcus neoformans by resident peritoneal macrophages in vitro. This was dependent upon opsonization of the yeasts with complement, 72 h of incubation with the cytokines for maximum effect, and the obligate involvement of the macrophage CR3 receptor. TNF-alpha and GM-CSF synergized at low concentrations, resulting in dramatic up-regulation of phagocytosis when compared to either cytokine alone. Supernatants from C. neoformans-specific T cells also increased macrophage phagocytic efficiency. Finally, the administration of neutralizing mAb specific for TNF-alpha and GM-CSF increased mortality in C. neoformans-infected mice, and induced the rapid progression of disease with involvement of the brain and meninges. We conclude that TNF-alpha and GM-CSF are potent regulators of complement-dependent phagocytosis by murine macrophages. Macrophage activation with these two cytokines can completely overcome the anti-phagocytic properties of the virulent yeasts. Our results, therefore, implicate TNF-alpha and GM-CSF as important mediators of resistance to encapsulated pathogens such as C. neoformans where ingestion of the organism is a critical process in host resistance.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antibodies, Monoclonal
  • Cryptococcosis / immunology
  • Cryptococcus neoformans / immunology*
  • Cytokines / pharmacology*
  • Dose-Response Relationship, Immunologic
  • Drug Synergism
  • Female
  • Germ-Free Life
  • Granulocyte-Macrophage Colony-Stimulating Factor / pharmacology*
  • Interferon-gamma / pharmacology
  • Interleukin-4 / pharmacology
  • Macrophage-1 Antigen / analysis
  • Macrophages / immunology*
  • Mice
  • Mice, Inbred CBA
  • Phagocytosis / drug effects*
  • T-Lymphocytes / immunology
  • Tumor Necrosis Factor-alpha / pharmacology*
  • Up-Regulation

Substances

  • Antibodies, Monoclonal
  • Cytokines
  • Macrophage-1 Antigen
  • Tumor Necrosis Factor-alpha
  • Interleukin-4
  • Interferon-gamma
  • Granulocyte-Macrophage Colony-Stimulating Factor