Wieland Catharina W, Siegmund Britta, Senaldi Giorgio, Vasil Michael L, Dinarello Charles A, Fantuzzi Giamila
Department of Medicine, University of Colorado Health Sciences Center, Denver, Colorado 80262, USA.
Infect Immun. 2002 Mar;70(3):1352-8. doi: 10.1128/IAI.70.3.1352-1358.2002.
Chronic pulmonary infection with Pseudomonas aeruginosa is common in cystic fibrosis (CF) patients. P. aeruginosa lipopolysaccharide (LPS), phosholipase C (PLC), and exotoxin A (ETA) were evaluated for their ability to induce pulmonary inflammation in mice following intranasal inoculation. Both LPS and PLC induced high levels of tumor necrosis factor alpha (TNF-alpha), interleukin 1 beta (IL-1 beta-6, gamma interferon (IFN-gamma), MIP-1 alpha MIP-2 in the lungs but did not affect IL-18 levels. ETA did not induce TNF-alpha and was a weak inducer of IL-1 beta, IL-6, macrophage inflammatory protein 1 alpha (MIP-1 alpha), and MIP-2. Remarkably, ETA reduced constitutive lung IL-18 levels. LPS was the only factor inducing IFN-gamma. LPS, PLC, and ETA all induced cell infiltration in the lungs. The role of interferon regulatory factor-1 (IRF-1) in pulmonary inflammation induced by LPS, PLC, and ETA was evaluated. When inoculated with LPS, IRF-1 gene knockout (IRF-1 KO) mice produced lower levels of TNF-alpha, IL-1 beta, and IFN-gamma than did wild-type (WT) mice. Similarly, a milder effect of ETA on IL-1 beta and IL-18 was observed for IRF-1 KO than for WT mice. In contrast, the cytokine response to PLC did not differ between WT and IRF-1 KO mice. Accordingly, LPS and ETA, but not PLC, induced expression of IRF-1 mRNA. IRF-1 deficiency had no effect on MIP-1 alpha and MIP-2 levels and on cell infiltration induced by LPS, PLC, or ETA. Flow cytometric evaluation of lung mononuclear cells revealed strongly reduced percentages of CD8(+) and NK cells in IRF-1 KO mice compared to percentages observed for WT mice. These data indicate that different virulence factors from P. aeruginosa induce pulmonary inflammation in vivo and that IRF-1 is involved in some of the cytokine responses to LPS and ETA.
铜绿假单胞菌慢性肺部感染在囊性纤维化(CF)患者中很常见。对铜绿假单胞菌脂多糖(LPS)、磷脂酶C(PLC)和外毒素A(ETA)经鼻接种后在小鼠中诱导肺部炎症的能力进行了评估。LPS和PLC均能在肺部诱导高水平的肿瘤坏死因子α(TNF-α)、白细胞介素1β(IL-1β)、IL-6、γ干扰素(IFN-γ)、巨噬细胞炎性蛋白1α(MIP-1α)和MIP-2,但不影响IL-18水平。ETA不诱导TNF-α,是IL-1β、IL-6、巨噬细胞炎性蛋白1α(MIP-1α)和MIP-2的弱诱导剂。值得注意的是,ETA降低了肺组织中组成性IL-18水平。LPS是唯一诱导IFN-γ的因子。LPS、PLC和ETA均能诱导肺部细胞浸润。评估了干扰素调节因子-1(IRF-1)在LPS、PLC和ETA诱导的肺部炎症中的作用。与野生型(WT)小鼠相比,接种LPS后,IRF-1基因敲除(IRF-1 KO)小鼠产生的TNF-α、IL-1β和IFN-γ水平较低。同样,观察到IRF-1 KO小鼠中ETA对IL-1β和IL-18的影响比对WT小鼠的影响更轻微。相比之下,WT小鼠和IRF-1 KO小鼠对PLC的细胞因子反应没有差异。因此,LPS和ETA而非PLC诱导IRF-1 mRNA的表达。IRF-1缺陷对MIP-1α和MIP-2水平以及LPS、PLC或ETA诱导的细胞浸润没有影响。对肺单核细胞的流式细胞术评估显示,与WT小鼠相比,IRF-1 KO小鼠中CD8(+)和NK细胞的百分比大幅降低。这些数据表明,铜绿假单胞菌的不同毒力因子在体内诱导肺部炎症,并且IRF-1参与了对LPS和ETA的一些细胞因子反应。