Pneumocystis carinii Cell Wall β-Glucans Initiate Macrophage Inflammatory Responses through NF-κB Activation

Frances Lebron, Robert Vassallo, Vishwajeet Puri, Andrew H. Limper

Research output: Contribution to journalArticle

89 Scopus citations

Abstract

β-Glucans are major structural components of fungi. We have recently reported that the pathogenic fungus Pneumocystis carinii assembles a β-glucan-rich cell wall that potently activates alveolar macrophages to release pro-inflammatory cytokines and chemokines. Purified P. carinii β-glucans predictably induce both cytokine generation and associated neutrophilic lung inflammation. Herein, we demonstrate that P. carinii β-glucan-induced macrophage stimulation results from activation of NF-κB. Although analogous to macrophage activation induced by bacterial lipopolysaccharide (LPS), P. carinii β-glucan-induced macrophage NF-κB activation exhibits distinctly different kinetics, with slower induction and longer duration compared with LPS stimulation. Macrophage activation in response to P. carinii β-glucan was also substantially inhibited with the NF-κB antagonist pyrrolidine dithiocarbamate. In addition to different kinetics of NF-κB activation, P. carinii κ-glucan and LPS also utilize different receptor systems to induce macrophage activation. Macrophages from Toll-like receptor 4-deficient and wild type mice produced equivalent amounts of tumor necrosis factor α when stimulated with P. carinii β-glucan. However, Toll-like receptor 4-deficient macrophages were refractory to stimulation with LPS. In contrast, MyD88-deficient macrophages exhibited a significant (though partial) blunted response to P. carinii β-glucan. These data demonstrate that P. carinii β-glucan acts as potent inducer of macrophage activation through NF-κB utilizing cellular receptors and signaling pathways distinct from LPS.

Original languageEnglish (US)
Pages (from-to)25001-25008
Number of pages8
JournalJournal of Biological Chemistry
Volume278
Issue number27
DOIs
StatePublished - Jul 4 2003

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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