Neutrophils Alter the Inflammatory Milieu by Signal-Dependent Translation of Constitutive Messenger RNAs

The mechanisms by which neutrophils, key effector cells of the innate immune system, express new gene products in inflammation are largely uncharacterized. We found that they rapidly translate constitutive mRNAs when activated, a previously unrecognized response. One of the proteins synthesized with...

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Published inProceedings of the National Academy of Sciences - PNAS Vol. 101; no. 18; pp. 7076 - 7081
Main Authors Lindemann, Stephan W., Yost, Christian C., Denis, Melvin M., McIntyre, Thomas M., Weyrich, Andrew S., Zimmerman, Guy A., White, Raymond L.
Format Journal Article
LanguageEnglish
Published United States National Academy of Sciences 04.05.2004
National Acad Sciences
Subjects
Actinomycin
Antibodies
Biological Sciences
Endothelial Cells
Gene expression regulation
Genetics
Human umbilical vein endothelial cells
Humans
Immune system
Inflammation
Inflammation - immunology
Inflammation - metabolism
Medical research
Medical treatment
Messenger RNA
Neutrophils
Neutrophils - immunology
Neutrophils - metabolism
Phosphorylation
Protein Biosynthesis - immunology
Protein Biosynthesis - physiology
Protein Kinases - metabolism
Receptors
Receptors, Interleukin-6 - genetics
Receptors, Interleukin-6 - metabolism
Ribonucleic acid
RNA
RNA, Messenger - immunology
RNA, Messenger - metabolism
Signal Transduction - immunology
Signal Transduction - physiology
TOR Serine-Threonine Kinases
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ISSN0027-8424
1091-6490
DOI10.1073/pnas.0401901101

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Summary:The mechanisms by which neutrophils, key effector cells of the innate immune system, express new gene products in inflammation are largely uncharacterized. We found that they rapidly translate constitutive mRNAs when activated, a previously unrecognized response. One of the proteins synthesized without a requirement for transcription is the soluble IL-6 receptor α, which translocates to endothelial cells and induces a temporal switch to mononuclear leukocyte recruitment. Its synthesis is regulated by a specialized translational control pathway that is inhibited by rapamycin, a bacterial macrolide with therapeutic efficacy in transplantation, inflammatory syndromes, and neoplasia. Signal-dependent translation in activated neutrophils may be a critical mechanism for alteration of the inflammatory milieu and a therapeutic target.
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Abbreviations: PMNs, polymorphonuclear leukocytes; mTOR, mammalian target of rapamycin; IL-6Rα, IL-6 receptor α subunit; PAF, platelet-activating factor; HUVEC, human umbilical vein endothelial cell; LPS, lipopolysaccharide; fMLP, N-formylmethionylleucylphenylalanine; EC, endothelial cells.
To whom correspondence should be addressed. E-mail: guy.zimmerman@hmbg.utah.edu.
Communicated by Raymond L. White, University of California at San Francisco, Emeryville, CA, March 22, 2004
Present address: Department of Medicine II, Johannes Gutenberg University, 55101 Mainz, Germany.
ISSN:0027-8424
1091-6490
DOI:10.1073/pnas.0401901101