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

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