Inhibiting Mer receptor tyrosine kinase suppresses STAT1, SOCS1/3, and NF-κB activation and enhances inflammatory responses in lipopolysaccharide-induced acute lung injury

Mer as an intrinsic feedback inhibitor of the TLR4‐driven immune responses during acute lung injury. Mer signaling participates in a novel inhibitory pathway in TLR activation. The purpose of the present study was to examine the role of Mer signaling in the down‐regulation of TLR4 activation‐driven...

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Bibliographic Details
Published in:Journal of leukocyte biology 2012-06, Vol.91 (6), p.921-932
Main Authors: Lee, Ye‐Ji, Han, Ji‐Young, Byun, Jiyeon, Park, Hyun‐Jeong, Park, Eun‐Mi, Chong, Young Hae, Cho, Min‐Sun, Kang, Jihee Lee
Format: Article
Language:English
Subjects:
Acute Lung Injury - chemically induced
Acute Lung Injury - genetics
Acute Lung Injury - immunology
alveolar macrophages
Animals
c-Mer Tyrosine Kinase
Cytokines - genetics
Cytokines - immunology
Enzyme Activation - drug effects
Enzyme Activation - genetics
Enzyme Activation - immunology
Gene Expression Regulation - drug effects
Gene Expression Regulation - genetics
Gene Expression Regulation - immunology
Inflammation Mediators - immunology
inflammatory mediators
Lipopolysaccharides - toxicity
Macrophages, Alveolar - immunology
Macrophages, Alveolar - pathology
Male
Matrix Metalloproteinase 9 - genetics
Matrix Metalloproteinase 9 - immunology
Mer signaling
Mice
Mice, Inbred BALB C
NF-kappa B - genetics
NF-kappa B - immunology
Phosphorylation - drug effects
Phosphorylation - genetics
Phosphorylation - immunology
Proto-Oncogene Proteins - genetics
Proto-Oncogene Proteins - immunology
pulmonary inflammation
Receptor Protein-Tyrosine Kinases - genetics
Receptor Protein-Tyrosine Kinases - immunology
soluble Mer
STAT1 Transcription Factor - genetics
STAT1 Transcription Factor - immunology
Suppressor of Cytokine Signaling 1 Protein
Suppressor of Cytokine Signaling 3 Protein
Suppressor of Cytokine Signaling Proteins - genetics
Suppressor of Cytokine Signaling Proteins - immunology
Toll-Like Receptor 4 - agonists
Toll-Like Receptor 4 - genetics
Toll-Like Receptor 4 - immunology
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Summary:Mer as an intrinsic feedback inhibitor of the TLR4‐driven immune responses during acute lung injury. Mer signaling participates in a novel inhibitory pathway in TLR activation. The purpose of the present study was to examine the role of Mer signaling in the down‐regulation of TLR4 activation‐driven immune responses in mice, i.t.‐treated with LPS, using the specific Mer‐blocking antibody. At 4 h and 24 h after LPS treatment, expression of Mer protein in alveolar macrophages and lung tissue decreased, sMer in BALF increased significantly, and Mer activation increased. Pretreatment with anti‐Mer antibody did not influence the protein levels of Mer and sMer levels. Anti‐Mer antibody significantly reduced LPS‐induced Mer activation, phosphorylation of Akt and FAK, STAT1 activation, and expression of SOCS1 and ‐3. Anti‐Mer antibody enhanced LPS‐induced inflammatory responses, including activation of the NF‐κB pathway; the production of TNF‐α, IL‐1β, and MIP‐2 and MMP‐9 activity; and accumulation of inflammatory cells and the total protein levels in BALF. These results indicate that Mer plays as an intrinsic feedback inhibitor of the TLR4‐ and inflammatory mediator‐driven immune responses during acute lung injury.
ISSN:0741-5400
1938-3673
DOI:10.1189/jlb.0611289