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J Biol Chem. 2003 Jul 4;278(27):25001-8. Epub 2003 Apr 25.

Pneumocystis carinii cell wall beta-glucans initiate macrophage inflammatory responses through NF-kappaB activation.

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Department of Immunology, Mayo Clinic and Foundation, Rochester, Minnesota 55905, USA.


beta-Glucans are major structural components of fungi. We have recently reported that the pathogenic fungus Pneumocystis carinii assembles a beta-glucan-rich cell wall that potently activates alveolar macrophages to release pro-inflammatory cytokines and chemokines. Purified P. carinii beta-glucans predictably induce both cytokine generation and associated neutrophilic lung inflammation. Herein, we demonstrate that P. carinii beta-glucan-induced macrophage stimulation results from activation of NF-kappaB. Although analogous to macrophage activation induced by bacterial lipopolysaccharide (LPS), P. carinii beta-glucan-induced macrophage NF-kappaB activation exhibits distinctly different kinetics, with slower induction and longer duration compared with LPS stimulation. Macrophage activation in response to P. carinii beta-glucan was also substantially inhibited with the NF-kappaB antagonist pyrrolidine dithiocarbamate. In addition to different kinetics of NF-kappaB activation, P. carinii beta-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 alpha when stimulated with P. carinii beta-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 beta-glucan. These data demonstrate that P. carinii beta-glucan acts as potent inducer of macrophage activation through NF-kappaB utilizing cellular receptors and signaling pathways distinct from LPS.

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