title: Pyocyanin and its precursor phenazine-1-carboxylic acid increase IL-8 and intercellular adhesion molecule-1 expression in human airway epithelial cells by oxidant-dependent mechanisms.
abstract: Pseudomonas aeruginosa secretes numerous factors that alter host cell function and may contribute to disease pathogenesis. Among recognized virulence factors is the redox-active phenazine pyocyanin. We have recently demonstrated that the precursor for pyocyanin, phenazine-1-carboxylic acid (PCA), increases oxidant formation and alters gene expression in human airway epithelial cells. We report in this work that PCA and pyocyanin increase expression of ICAM-1 both in vivo and in vitro. Moreover, phenazines enhanced cytokine-dependent increases in IL-8 and ICAM-1. Antioxidant intervention studies indicated both similarities and differences between PCA and pyocyanin. The thiol antioxidant N-acetyl cysteine, extracellular catalase, and inducible NO synthase inhibitors inhibited ICAM-1 and IL-8 increases in response to both phenazines. However, pyocyanin was significantly more sensitive to N-acetylcysteine inhibition. Interestingly, hydroxyl radical scavengers inhibited the response to pyocyanin, but not to PCA. These studies suggest that P. aeruginosa phenazines coordinately up-regulate chemokines (IL-8) and adhesion molecules (ICAM-1) by mechanisms that are, at least in part, oxidant dependent. However, results indicate that the mechanisms by which PCA and pyocyanin exert their effects are not identical, and not all antioxidant interventions are equally effective in inhibiting phenazine-mediated proinflammatory effects.
authors.affiliation: Department of Internal Medicine, University of Iowa Roy J. and Lucille A. Carver College of Medicine and Iowa City Veterans Affairs Medical Center, Iowa City, IA 52246, USA.
authors.forename: Dwight C
authors.initials: DC
authors.lastname: Look
authors.forename: Lynn L
authors.initials: LL
authors.lastname: Stoll
authors.forename: Sara A
authors.initials: SA
authors.lastname: Romig
authors.forename: Alicia
authors.initials: A
authors.lastname: Humlicek
authors.forename: Bradley E
authors.initials: BE
authors.lastname: Britigan
authors.forename: Gerene M
authors.initials: GM
authors.lastname: Denning
mesh_terms: D000975:Antioxidants / Q000494:pharmacology; D002478:Cells, Cultured; D004847:Epithelial Cells; D016166:Free Radical Scavengers / Q000494:pharmacology; D006801:Humans; D018799:Intercellular Adhesion Molecule-1 / Q000096:biosynthesis*; D016209:Interleukin-8 / Q000096:biosynthesis*; D010084:Oxidation-Reduction; D010619:Phenazines / Q000494:pharmacology; D011550:Pseudomonas aeruginosa / Q000472:pathogenicity; D011710:Pyocyanine / Q000494:pharmacology*; D020545:Respiratory Mucosa / Q000166:cytology / Q000276:immunology / Q000378:metabolism*; D015854:Up-Regulation / Q000187:drug effects; D037521:Virulence Factors / Q000494:pharmacology
chemical_list: D000975:Antioxidants; D016166:Free Radical Scavengers; D016209:Interleukin-8; D010619:Phenazines; D037521:Virulence Factors; D018799:Intercellular Adhesion Molecule-1; C037165:1-phenazinecarboxylic acid; D011710:Pyocyanine