Elevated inflammatory response in caveolin-1-deficient mice with Pseudomonas aeruginosa infection is mediated by STAT3 protein and Nuclear Factor κB (NF-κB)

Kefei Yuan, Canhua Huang, John Fox, Madeleine Gaid, Andrew Weaver, Guoping Li, Brij B. Singh, Hongwei Gao, Min Wu

Research output: Contribution to journalArticlepeer-review

67 Scopus citations

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-1KOmice 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, downregulating 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.

Original languageEnglish (US)
Pages (from-to)21814-21825
Number of pages12
JournalJournal of Biological Chemistry
Volume286
Issue number24
DOIs
StatePublished - Jun 17 2011
Externally publishedYes

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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