Pseudomonas pyocyanin increases interleukin-8 expression by human airway epithelial cells

Pseudomonas aeruginosa, an opportunistic human pathogen, causes acute pneum onia in patients with hospital-acquired infections and is commonly associat ed,vith chronic lung disease in individuals with cystic fibrosis (CF), Evid ence suggests that the pathophysiological effects of P, aeruginosa are medi ated in part by virulence factors secreted by the bacterium. Among these fa ctors is pyocyanin, a redox active compound that increases intracellular ox idant stress. We find that pyocyanin increases release of interleukin-8 (IL -8) by both normal and CF airway epithelial cell lines and by primary airwa y epithelial cells, Moreover, pyocyanin synergizes with the inflammatory cy tokines tumor necrosis factor alpha and IL-1 alpha. RNase protection assays indicate that increased IL-8 release is accompanied by increased levels of IL-8 mRNA, The antioxidant n-acetyl cysteine, general inhibitors of protei n tyrosine kinases, and specific inhibitors of mitogen-activated protein ki nases diminish pyocyanin-dependent increases in IL-S release. Conversely, i nhibitors of protein kinases C (PEC) and PKA have no effect, In contrast to its effects on IL-8 expression, pyocyanin inhibits cytokine-dependent expr ession of the monocyte/macrophage/T-cell chemokine RANTES, Increased releas e of IL-g, a potent neutrophil chemoattractant, in response to pyocyanin co uld contribute to the marked infiltration of neutrophils and subsequent neu trophil-mediated tissue damage that are observed in Pseudomonas-associated lung disease.