Abstract
Pseudomonas aeruginosa is known to play a role in many human diseases. Therefore, examining the negative control mechanisms of tight junction protein ZO-1 on the exotoxin LPS of P. aeruginosa-induced diseases could be critical in the development of novel therapeutics. We found that ZO-1 expression dramatically decreased in inflammatory human lung tissues. Interestingly, PDZ1 deletion of the PDZ domain in the ZO-1 protein dramatically decreased LPS-induced F-actin formation and increased the expression of genes for pro-inflammatory cytokines, but not PDZ2 and PDZ3 of the ZO-1 protein. We also found that the consensus PDZ peptide (based on PDZ1) of ZO-1 down-regulates the expression of pro-inflammatory cytokine genes and F-actin formation; in contrast, the GG24,25AA mutant PDZ peptide cannot control these genes. LPS activates IL-8 secretion extracellularly in a time-dependent manner, while the secretion is inhibited by PDZ peptide. Whereas increased IL-8 secretion by LPS activates the CXCR2 receptor, overexpressed RGS12 negatively regulates LPS-induced CXCR2/IL-8 signaling. The PDZ peptide also decreases LPS-induced inflammatory cell populations, pro-inflammatory cytokine gene expression, and TEER in bronchoalveolar lavage fluid and cultured alveolar macrophages. Collectively, we suggest that the PDZ peptide may be a potential therapeutic for bacteria-induced respiratory diseases.
Highlights
IntroductionExamining the negative control mechanisms of tight junction protein zonula occludens (ZO)-1 on the exotoxin LPS of P. aeruginosainduced diseases could be critical in the development of novel therapeutics
Pseudomonas aeruginosa is known to play a role in many human diseases
Overexpression of zonula occludens (ZO)-1 appears to increase the level of inflammation, ZO-1 diminished the level of pro-inflammatory cytokine gene expression at later stages of inflammation (24 h; data not shown)
Summary
Examining the negative control mechanisms of tight junction protein ZO-1 on the exotoxin LPS of P. aeruginosainduced diseases could be critical in the development of novel therapeutics. PDZ1 deletion of the PDZ domain in the ZO-1 protein dramatically decreased LPS-induced F-actin formation and increased the expression of genes for pro-inflammatory cytokines, but not PDZ2 and PDZ3 of the ZO-1 protein. Respiratory infections are more lethal for patients with inflammatory conditions, such as asthma or COPD, studies examining the negative control mechanisms of P. aeruginosa-induced diseases are critical to the development of novel therapeutic medications. Of the mechanisms for GPCR desensitization, the regulators of G-protein signaling (RGS) family are negative regulators of specific GPCR s ignals[13,14]. The mechanisms by which RGS proteins can desensitize the CXCR2-induced pathway activated by components of P. aeruginosa remain to be examined
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
