title: Elevated inflammatory response in caveolin-1-deficient mice with Pseudomonas aeruginosa infection is mediated by STAT3 protein and nuclear factor kappaB (NF-kappaB).
abstract: Caveolin-1 (Cav-1), an important composition protein within the flask-shaped membrane invaginations termed caveolae, may play a role in host defense against infections. However, the phenotype in Pseudomonas aeruginosa-infected cav1 knock-out (KO) mice is still unresolved, and the mechanism involved is almost entirely unknown. Using a respiratory infection model, we confirmed a crucial role played by Cav-1 in host defense against this pathogen because Cav-1 KO mice showed increased mortality, severe lung injury, and systemic dissemination as compared with wild-type (WT) littermates. In addition, cav1 KO mice exhibited elevated inflammatory cytokines (IL-6, TNF-α, and IL-12a), decreased phagocytic ability of macrophages, and increased superoxide release in the lung, liver, and kidney. We further studied relevant cellular signaling processes and found that STAT3 and NF-κB are markedly activated. Our data revealed that the Cav-1/STAT3/NF-κB axis is responsible for a dysregulated cytokine response, which contributes to increased mortality and disease progression. Moreover, down-regulating Cav-1 in cell culture with a dominant negative strategy demonstrated that STAT3 activation was essential for the translocation of NF-κB into the nucleus, confirming the observations from cav1 KO mice. Collectively, our studies indicate that Cav-1 is critical for inflammatory responses regulating the STAT3/NF-κB pathway and thereby impacting P. aeruginosa infection.
authors.affiliation: State Key Laboratory for Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, China.
authors.forename: Kefei
authors.initials: K
authors.lastname: Yuan
authors.forename: Canhua
authors.initials: C
authors.lastname: Huang
authors.forename: John
authors.initials: J
authors.lastname: Fox
authors.forename: Madeleine
authors.initials: M
authors.lastname: Gaid
authors.forename: Andrew
authors.initials: A
authors.lastname: Weaver
authors.forename: Guoping
authors.initials: G
authors.lastname: Li
authors.forename: Brij B
authors.initials: BB
authors.lastname: Singh
authors.forename: Hongwei
authors.initials: H
authors.lastname: Gao
authors.forename: Min
authors.initials: M
authors.lastname: Wu
mesh_terms: D000818:Animals; D051242:Caveolin 1 / Q000235:genetics*; D005799:Genes, Dominant; D007249:Inflammation; D018664:Interleukin-12 / Q000378:metabolism; D015850:Interleukin-6 / Q000378:metabolism; D008168:Lung / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D016328:NF-kappa B / Q000378:metabolism*; D018384:Oxidative Stress; D011552:Pseudomonas Infections / Q000235:genetics* / Q000378:metabolism; D011550:Pseudomonas aeruginosa / Q000378:metabolism*; D050796:STAT3 Transcription Factor / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: D051242:Caveolin 1; D015850:Interleukin-6; D016328:NF-kappa B; D050796:STAT3 Transcription Factor; C494087:Stat3 protein, mouse; D014409:Tumor Necrosis Factor-alpha; D018664:Interleukin-12