PseudomonasPyocyanin Increases Interleukin-8 Expression by Human Airway Epithelial Cells

Abstract

Pseudomonas aeruginosa, an opportunistic human pathogen, causes acute pneumonia in patients with hospital-acquired infections and is commonly associated with chronic lung disease in individuals with cystic fibrosis (CF). Evidence suggests that the pathophysiological effects of P. aeruginosa are mediated in part by virulence factors secreted by the bacterium. Among these factors is pyocyanin, a redox active compound that increases intracellular oxidant stress. We find that pyocyanin increases release of interleukin-8 (IL-8) by both normal and CF airway epithelial cell lines and by primary airway epithelial cells. Moreover, pyocyanin synergizes with the inflammatory cytokines tumor necrosis factor alpha and IL-1α. 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 protein tyrosine kinases, and specific inhibitors of mitogen-activated protein kinases diminish pyocyanin-dependent increases in IL-8 release. Conversely, inhibitors of protein kinases C (PKC) and PKA have no effect. In contrast to its effects on IL-8 expression, pyocyanin inhibits cytokine-dependent expression of the monocyte/macrophage/T-cell chemokine RANTES. Increased release of IL-8, a potent neutrophil chemoattractant, in response to pyocyanin could contribute to the marked infiltration of neutrophils and subsequent neutrophil-mediated tissue damage that are observed inPseudomonas-associated lung disease.

The role of quorum sensing in chronic cystic fibrosisPseudomonas aeruginosainfections

“…This cell influx helps to resolve inflammation whereas any delay can prolong the inflammatory state. Treatment with pyocyanin decreases the level of RANTES released from epithelial cells (Denning et al, 1998).…”

“…In the lungs of sheep, pyocyanin causes an inflammatory response characterized by an influx of neutrophils (Lauredo et al, 1998). At concentrations 20-fold lower than the levels found in the sputum of some CF patients, pyocyanin increases the release from human airway epithelia of IL-8, a major chemoattractant for neutrophils (Denning et al, 1998). RANTES [chemokine ligand (CCL)-5] is a chemokine, expressed 3-5 days following T cell activation, that attracts T-cell monocytes and eosinophils to sites of inflammation.…”

Pseudomonas aeruginosa: new insights into pathogenesis and host defenses

“…Purified pyocyanin has been shown in vitro to induce apoptosis in neutrophils as well as inhibit the phagocytosis of apoptotic bodies by macrophages (Lau et al, 2004;Bianchi et al, 2008). It is also able to modulate the expression of the chemokines IL-8 and RANTES by airway epithelial cells (Denning et al, 1998) and suppress cilia beating. Along with rhamnolipids, the production of pyocyanin has been shown to be partly controlled by the oxidative stress RR, OxyR, and is therefore thought to play a protective role against the reactive oxygen and nitrogen species produced by phagocytic cells during infection (Lau et al, 2005;Vinckx et al, 2010).…”

Non-invasive assessment of upper and lower airway infection and inflammation in CF patients

“…29,30 Matrix metalloprotease concentrations are also altered by treatment regimens, including with fluticasone and roxithromycin. 31,32 P. aeruginosa colonization of the UAW resulted in increased expression of RANTES, a chemokine that promotes the transmigration of monocytes, lymphocytes, and eosinophils, with its transcription induced by P. aeruginosa exoenzyme S. 33 In contrast, P. aeruginosa colonization of the LAW did not up-regulate RANTES expression, 34,35 a difference that may be due to the adaptive mechanisms of P. aeruginosa. While suppression of RANTES in the LAW may prevent the eradication of P. aeruginosa, up-regulation in the UAW may eliminate competitive bacteria, including S. aureus, sustaining P. aeruginosa colonization in the UAW.…”