The anti-microbial peptide TP359 attenuates inflammation in human lung cells infected with Pseudomonas aeruginosa via TLR5 and MAPK pathways
Autor: | Shree R. Singh, Shreekumar R. Pillai, Robert O. Emeh, Mona K. Bakeer, Donald R. Owen, Ejovwoke F. Dosunmu, Saurabh Dixit, Mamie T. Coats, Vida A. Dennis |
---|---|
Jazyk: | angličtina |
Rok vydání: | 2017 |
Předmět: |
0301 basic medicine
Cell signaling Lipopolysaccharide Physiology lcsh:Medicine Signal transduction medicine.disease_cause Pathology and Laboratory Medicine Immune Receptors Biochemistry Epithelium chemistry.chemical_compound Animal Cells Immune Physiology Microbial Physiology Medicine and Health Sciences Bacterial Physiology lcsh:Science Immune Response Toll-like Receptors Innate Immune System Multidisciplinary Immune System Proteins biology Pseudomonas Aeruginosa Signaling cascades 3. Good health Bacterial Pathogens Anti-Bacterial Agents Medical Microbiology Cytokines Tumor necrosis factor alpha medicine.symptom Pathogens Cellular Types Anatomy Research Article Cell biology MAPK signaling cascades MAP Kinase Signaling System p38 mitogen-activated protein kinases 030106 microbiology Immunology Blotting Western Inflammation Microbiology Proinflammatory cytokine 03 medical and health sciences Signs and Symptoms Diagnostic Medicine Pseudomonas medicine Pneumonia Bacterial Humans Pseudomonas Infections Microbial Pathogens Secretion Bacteria Dose-Response Relationship Drug Pseudomonas aeruginosa Interleukin-6 Tumor Necrosis Factor-alpha lcsh:R Interleukin-8 Organisms Biology and Life Sciences Proteins Epithelial Cells Bacteriology Molecular Development Toll-Like Receptor 5 030104 developmental biology Biological Tissue chemistry TLR5 A549 Cells Immune System biology.protein lcsh:Q Physiological Processes Flagellin Developmental Biology Antimicrobial Cationic Peptides |
Zdroj: | PLoS ONE PLoS ONE, Vol 12, Iss 5, p e0176640 (2017) |
ISSN: | 1932-6203 |
Popis: | Pseudomonas aeruginosa infection induces vigorous inflammatory mediators secreted by epithelial cells, which do not necessarily eradicate the pathogen. Nonetheless, it reduces lung function due to significant airway damage, most importantly in cystic fibrosis patients. Recently, we published that TP359, a proprietary cationic peptide had potent bactericidal effects against P. aeruginosa, which were mediated by down-regulating its outer membrane biogenesis genes. Herein, we hypothesized that TP359 bactericidal effects could also serve to regulate P. aeruginosa-induced lung inflammation. We explored this hypothesis by infecting human A549 lung cells with live P. aeruginosa non-isogenic, mucoid and non-mucoid strains and assessed the capacity of TP359 to regulate the levels of elicited TNFα, IL-6 and IL-8 inflammatory cytokines. In all instances, the mucoid strain elicited higher concentrations of cytokines in comparison to the non-mucoid strain, and TP359 dose-dependently down-regulated their respective levels, suggesting its regulation of lung inflammation. Surprisingly, P. aeruginosa flagellin, and not its lipopolysaccharide moiety, was the primary inducer of inflammatory cytokines in lung cells, which were similarly down-regulated by TP359. Blocking of TLR5, the putative flagellin receptor, completely abrogated the capacity of infected lung cells to secrete cytokines, underscoring that TP359 regulates inflammation via the TLR5-dependent signaling pathway. Downstream pathway-specific inhibition studies further revealed that the MAPK pathway, essentially p38 and JNK are necessary for induction of P. aeruginosa elicited inflammatory cytokines and their down-regulation by TP359. Collectively, our data provides evidence to support exploring the relevancy of TP359 as an anti-microbial and anti-inflammatory agent against P. aeruginosa for clinical applications. |
Databáze: | OpenAIRE |
Externí odkaz: |