TY - JOUR
T1 - Pneumocystis carinii Cell Wall β-Glucans Initiate Macrophage Inflammatory Responses through NF-κB Activation
AU - Lebron, Frances
AU - Vassallo, Robert
AU - Puri, Vishwajeet
AU - Limper, Andrew H.
PY - 2003/7/4
Y1 - 2003/7/4
N2 - 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.
AB - 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.
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U2 - 10.1074/jbc.M301426200
DO - 10.1074/jbc.M301426200
M3 - Article
C2 - 12716885
AN - SCOPUS:0041589276
SN - 0021-9258
VL - 278
SP - 25001
EP - 25008
JO - Journal of Biological Chemistry
JF - Journal of Biological Chemistry
IS - 27
ER -