Pneumocystis carinii cell wall beta-glucans initiate macrophage inflammatory responses through NF-kappaB activation.
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.
Lebron
Frances
F
Department of Immunology, Mayo Clinic and Foundation, Rochester, Minnesota 55905, USA.
Vassallo
Robert
R
Puri
Vishwajeet
V
Limper
Andrew H
AH
D000818:Animals; D002460:Cell Line; D005936:Glucans / Q000378:metabolism* / Q000494:pharmacology; D008262:Macrophage Activation / Q000187:drug effects; D008264:Macrophages / Q000378:metabolism* / Q000382:microbiology; D051379:Mice; D016328:NF-kappa B / Q000378:metabolism*; D011010:Pneumocystis / Q000378:metabolism*; D051381:Rats; D015398:Signal Transduction / Q000187:drug effects
D005936:Glucans; D016328:NF-kappa B