title: Type III Secretion System of Pseudomonas aeruginosa Affects Matrix Metalloproteinase 12 (MMP-12) and MMP-13 Expression via Nuclear Factor κB Signaling in Human Carcinoma Epithelial Cells and a Pneumonia Mouse Model.
abstract: The type III secretion system (T3SS) in Pseudomonas aeruginosa has been linked to severe disease and poor clinical outcomes in animal and human studies. We aimed to investigate whether the ExoS and ExoT effector proteins of P. aeruginosa affect the expression of matrix metalloproteinase 12 (MMP-12) and MMP-13 via nuclear factor κB (NF-κB) signaling pathways. To understand the T3SS, we used ΔExoS, ΔExoT, and ExsA::Ω mutants, as well as P. aeruginosa strain K (PAK)-stimulated NCI-H292 cells. We investigated the effects of ΔExoS, ΔExoT, and ExsA::Ω on the development of pneumonia in mouse models. We examined the effects of ΔExoS, ΔExoT, and ExsA::Ω on MMP-12 and MMP-13 production in NCI-H292 cells. ΔExoS and ΔExoT markedly decreased the neutrophil count in bronchoalveolar lavage fluid, with a reduction in proinflammatory mediators, MMP-12, and MMP-13. ΔExoS and ΔExoT reduced NF-κB phosphorylation, together with MMP-12 and MMP-13 expression in PAK-infected mouse models and NCI-H292 cells. To conclude, P. aeruginosa infection induced the expression of MMPs, and P. aeruginosa T3SS appeared to be a key player in MMP-12 and MMP-13 expression, which is further controlled by NF-κB signaling. These findings might be useful in devising a novel therapeutic approach to chronic pulmonary infections that involves decreasing the ExoS and ExoT levels.
authors.affiliation: Natural Medicine Research Center, Korea Research Institute of Bioscience and Biotechnology, Cheongju-si College of Life Sciences and Biotechnology, Korea University, Seoul.
authors.forename: Ji-Won
authors.initials: JW
authors.lastname: Park
authors.affiliation: Department of Biotechnology and Bioinformatics, Korea University, Sejong.
authors.forename: Yong-Jae
authors.initials: YJ
authors.lastname: Kim
authors.affiliation: College of Veterinary Medicine, Chonnam National University, Gwangju.
authors.forename: In-Sik
authors.initials: IS
authors.lastname: Shin
authors.affiliation: Natural Medicine Research Center, Korea Research Institute of Bioscience and Biotechnology, Cheongju-si Department of Toxicology, College of Pharmacy, Chungnam National University, Daejeon.
authors.forename: Ok-Kyoung
authors.initials: OK
authors.lastname: Kwon
authors.affiliation: Division of Life sciences, Korea Polar Research Institute, Incheon.
authors.forename: Ju Mi
authors.initials: JM
authors.lastname: Hong
authors.affiliation: College of Veterinary Medicine, Chonnam National University, Gwangju.
authors.forename: Na-Rae
authors.initials: NR
authors.lastname: Shin
authors.affiliation: Natural Medicine Research Center, Korea Research Institute of Bioscience and Biotechnology, Cheongju-si.
authors.forename: Sei-Ryang
authors.initials: SR
authors.lastname: Oh
authors.affiliation: Department of Biotechnology and Bioinformatics, Korea University, Sejong.
authors.forename: Un-Hwan
authors.initials: UH
authors.lastname: Ha
authors.affiliation: College of Life Sciences and Biotechnology, Korea University, Seoul.
authors.forename: Jae-Hong
authors.initials: JH
authors.lastname: Kim
authors.affiliation: Natural Medicine Research Center, Korea Research Institute of Bioscience and Biotechnology, Cheongju-si.
authors.forename: Kyung-Seop
authors.initials: KS
authors.lastname: Ahn
mesh_terms: D036002:ADP Ribose Transferases / Q000235:genetics / Q000378:metabolism; D000818:Animals; D001426:Bacterial Proteins / Q000235:genetics / Q000378:metabolism; D001427:Bacterial Toxins / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D004847:Epithelial Cells / Q000382:microbiology*; D020690:GTPase-Activating Proteins / Q000235:genetics / Q000378:metabolism; D055786:Gene Knockout Techniques; D054884:Host-Pathogen Interactions; D006801:Humans; D053508:Matrix Metalloproteinase 12 / Q000096:biosynthesis* / Q000378:metabolism; D053509:Matrix Metalloproteinase 13 / Q000096:biosynthesis* / Q000378:metabolism; D051379:Mice; D016328:NF-kappa B / Q000378:metabolism*; D018410:Pneumonia, Bacterial / Q000382:microbiology / Q000473:pathology*; D011550:Pseudomonas aeruginosa / Q000472:pathogenicity*; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism; D000069296:Type III Secretion Systems / Q000378:metabolism*
chemical_list: D001426:Bacterial Proteins; D001427:Bacterial Toxins; C477521:ExoT protein, Pseudomonas aeruginosa; C095093:ExsA protein, Pseudomonas aeruginosa; D020690:GTPase-Activating Proteins; D016328:NF-kappa B; D011993:Recombinant Fusion Proteins; D015534:Trans-Activators; D000069296:Type III Secretion Systems; D036002:ADP Ribose Transferases; C444820:exoenzyme S; D053509:Matrix Metalloproteinase 13; C507081:Mmp13 protein, mouse; C507122:MMP12 protein, human; D053508:Matrix Metalloproteinase 12; C000602031:matrix metallopeptidase 12, mouse
keywords: MMP-13; NCI-H292; NF-κB; Pneumonia; Pseudomonas aeruginosa; matrix metalloproteinase (MMP)-12; type III secretion system