Pneumocystis cell wall beta-glucans stimulate alveolar epithelial cell chemokine generation through nuclear...

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.