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.