Pneumocystis cell wall β-glucans stimulate alveolar epithelial cell chemokine generation through nuclear factor-κB-dependent mechanisms
Pneumocystis cell wall β-glucans stimulate alveolar epithelial cell chemokine generation through nuclear factor-κB-dependent mechanisms
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DOI：
10.1165/rcmb.2004-0300oc
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发表时间：
2005-06-01
影响因子：
6.4
通讯作者：
Limper, AH
中科院分区：
文献类型：
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作者：
Evans, SE;Hahn, PY;Limper, AH
肺孢子虫肺炎期间，强烈的炎症反应与呼吸衰竭相关。肺泡上皮细胞（AECs）促进肺孢子虫的附着和增殖，但在肺炎期间也显著促进宿主精氨酸介导的炎症。最近的研究表明，AEC产生巨噬细胞炎性蛋白-2（MIP-2）和肿瘤坏死因子-α（TNF-α）后，与卡氏肺孢子虫的挑战。核因子-κ B（NF-κ B）是一种普遍存在的转录因子，对调节促炎细胞因子的表达至关重要。在此，我们评估了大鼠AEC NF-κ B对卡氏肺孢子虫β-葡聚糖细胞壁组分（PCBG）激发的反应。PCBG攻击后，p65 NF-κ B B显著核转位。NF-κ B活化部分通过蛋白激酶C（PKC）信号通路介导。PCBG刺激AEC也可诱导MIP-2和TNF-α mRNA的产生，抑制NF-κ B可改善这种反应。MIP-2蛋白表达也显著增加PCBG挑战，在一种方式，显着减弱PKC和NF-κ B抑制。这些数据进一步表明，AEC趋化因子的反应不是由最近描述的dectin-1受体介导的，而是涉及细胞表面乳糖神经酰胺的参与。这些数据支持肺孢子虫肺炎期间AEC在宿主反应中的重要作用，并进一步表明β-葡聚糖通过NF-κ B依赖性机制诱导炎性细胞因子产生。
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-kappa B (NF-kappa B) is a ubiquitous transcription factor critical for regulation of proinflammatory cytokine expression. Herein, we assess rat AEC NF-kappa B responses to challenge with a P. carinii P-glucan cell wall component (PCBG). Prominent nuclear translocation of p65 NF-kappa B was demonstrated following PCBG challenge. NF-kappa 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-alpha mRNA production, a response that was ameliorated by NF-kappa 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-kappa 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 beta-glucan induces inflammatory cytokine production through NF-kappa B-dependent mechanisms.