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miR‐150 prevents pulmonary inflammation by regulating Interleukin‐1R associated kinase‐2 downstream of focal adhesion kinase
Author(s) -
Rajput Charu,
Tauseef Mohammad,
Yazbeck Pascal,
Thennes Tracy,
Mehta Dolly
Publication year - 2012
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.26.1_supplement.671.10
Subject(s) - inflammation , cancer research , focal adhesion , pulmonary edema , lung , kinase , medicine , microbiology and biotechnology , immunology , biology , signal transduction
Pulmonary inflammation and severe edema developing post‐sepsis are the main hallmarks of Acute Lung Injury (ALI). We have shown that tamoxifen‐induced endothelial‐specific deletion of FAK led to disruption of lung vascular barrier and generation of pro‐inflammatory cytokines mimicking early phase of ALI. In this study, we addressed the role of microRNA (miR)‐150 in regulating lung inflammation downstream of FAK based on the tenet that the plasma level of mir‐150 were found to be decreased in septic patients. FAK deleted mice lungs showed markedly suppressed miR‐150 expression in miR‐microarray. We confirmed these findings in EC‐FAK −/− lungs and FAK‐depleted human endothelial cells (ECs) using mir‐150 specific primers. Furthermore, we show that in WT mice, miR‐150 expression decreased following LPS‐induced lung injury and subsequently was restored during resolution of lung inflammation. However, in miR‐150 −/− mice, LPS persistently induced edema formation. These findings were recapitulated in WT mice where alteration of miR‐150 activity modulated edema formation and inflammation. We identified interleukin‐1R‐associated kinase‐2 (IRAK2), a critical mediator LPS‐induced inflammation, as a downstream effector of mir‐150. We showed augmented IRAK2 levels in EC‐FAK − / − and miR‐150 −/− mice lungs as well as FAK knock down ECs. The IRAK2 3′UTR luciferase reporter assay confirmed it as a miR150 target. Our results demonstrate a critical role of miR‐150 downstream of FAK in dampening pulmonary inflammation by targeting IRAK2.