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Pneumocystis Cell Wall ß-Glucans Stimulate Alveolar Epithelial Cell Chemokine Generation through Nuclear Factor-B–Dependent Mechanisms

Thoracic Diseases Research Unit, Division of Pulmonary, Critical Care and Internal Medicine, Department of Medicine; Department of Immunology; and Department of Biochemistry and Molecular Biology, Mayo Clinic College of Medicine, Rochester, Minnesota

Correspondence and requests for reprints should be addressed to Andrew H. Limper, M.D., 8-24 Stabile Building, Mayo Clinic, Rochester, MN 55905. E-mail: limper.andrew{at}mayo.edu

Exuberant inflammatory responses are associated with respiratory failure during Pneumocystis pneumonia. Alveolar epithelial cells (AECs) promote Pneumocystis attachment and proliferation, but also contribute prominently to host cytokine-mediated inflammation during pneumonia. Recent investigations indicate that AECs produce macrophage inflammatory protein-2 (MIP-2) and tumor necrosis factor- (TNF-) following challenge with Pneumocystis carinii. Nuclear factor-B (NF-B) is a ubiquitous transcription factor critical for regulation of proinflammatory cytokine expression. Herein, we assess rat AEC NF-B responses to challenge with a P. carinii ß-glucan cell wall component (PCBG). Prominent nuclear translocation of p65 NF-B was demonstrated following PCBG challenge. NF-B activation was in part mediated through Protein Kinase C (PKC) signaling pathways. PCBG challenge of AECs was also shown to induce MIP-2 and TNF- mRNA production, a response that was ameliorated by NF-B inhibition. MIP-2 protein expression was also dramatically increased by PCBG challenge, in a manner that was significantly attenuated by both PKC and NF-B inhibition. The data further demonstrate that AEC chemokine responses were not mediated by the recently described dectin-1 receptor, but instead involved participation of cell surface lactosylceramide. These data support a significant role for AECs in host responses during Pneumocystis pneumonia, and further indicate that ß-glucan induces inflammatory cytokine production through NF-B–dependent mechanisms.

Key Words: pneumocystis • alveolar epithelial cells • nuclear factor-B • chemokines

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