title: Pneumocystis cell wall beta-glucans stimulate alveolar epithelial cell chemokine generation through nuclear factor-kappaB-dependent mechanisms.
abstract: 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-alpha (TNF-alpha) following challenge with Pneumocystis carinii. Nuclear factor-kappaB (NF-kappaB) is a ubiquitous transcription factor critical for regulation of proinflammatory cytokine expression. Herein, we assess rat AEC NF-kappaB responses to challenge with a P. carinii beta-glucan cell wall component (PCBG). Prominent nuclear translocation of p65 NF-kappaB was demonstrated following PCBG challenge. NF-kappaB 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-alpha mRNA production, a response that was ameliorated by NF-kappaB inhibition. MIP-2 protein expression was also dramatically increased by PCBG challenge, in a manner that was significantly attenuated by both PKC and NF-kappaB 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 beta-glucan induces inflammatory cytokine production through NF-kappaB-dependent mechanisms.
authors.affiliation: Department of Medicine, Mayo Clinic College of Medicine, Rochester, Minnesota, USA.
authors.forename: Scott E
authors.initials: SE
authors.lastname: Evans
authors.forename: Peter Y
authors.initials: PY
authors.lastname: Hahn
authors.forename: Frances
authors.initials: F
authors.lastname: McCann
authors.forename: Theodore J
authors.initials: TJ
authors.lastname: Kottom
authors.forename: Zvezdana Vuk
authors.initials: ZV
authors.lastname: Pavlovic'
authors.forename: Andrew H
authors.initials: AH
authors.lastname: Limper
mesh_terms: D000818:Animals; D015703:Antigens, CD / Q000378:metabolism; D054426:Chemokine CXCL2; D018925:Chemokines / Q000378:metabolism*; D015870:Gene Expression / Q000276:immunology; D066298:In Vitro Techniques; D007790:Lactosylceramides / Q000378:metabolism; D037181:Lectins, C-Type; D008565:Membrane Proteins / Q000378:metabolism; D015846:Monokines / Q000235:genetics / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism*; D009419:Nerve Tissue Proteins / Q000378:metabolism; D045363:Pneumocystis carinii / Q000378:metabolism*; D011020:Pneumonia, Pneumocystis / Q000276:immunology* / Q000378:metabolism; D011493:Protein Kinase C / Q000378:metabolism; D011650:Pulmonary Alveoli / Q000166:cytology / Q000276:immunology / Q000382:microbiology; D051381:Rats; D020545:Respiratory Mucosa / Q000166:cytology / Q000276:immunology / Q000382:microbiology*; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics; D047071:beta-Glucans / Q000378:metabolism*; D000099181:Dectin-1
chemical_list: D015703:Antigens, CD; D054426:Chemokine CXCL2; D018925:Chemokines; D007790:Lactosylceramides; D037181:Lectins, C-Type; D008565:Membrane Proteins; D015846:Monokines; D016328:NF-kappa B; D009419:Nerve Tissue Proteins; D011493:Protein Kinase C; D014409:Tumor Necrosis Factor-alpha; D047071:beta-Glucans; D000099181:Dectin-1; C009744:CDw17 antigen