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Cited by 423Immune Response and InflammationMicroRNA in disease regulationInflammasome and immune disorders

miR-146a Is Critical for Endotoxin-induced Tolerance

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Nahid, Md A., Pauley, Kaleb M., Satoh, Minoru, Chan, Edward K.L.·2009·Journal of Biological Chemistry
DOI 10.1074/jbc.m109.056317PMC PMC2787321
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Abstract

The human toll-like receptor 4 (TLR4) pathway is activated in response to lipopolysaccharide (LPS), and subsequent signal transductions lead to the production of cytokines such as tumor necrosis factor-alpha (TNF-alpha) by innate immune cells. Defects in innate immune response may contribute to the overproduction of TNF-alpha leading to systemic inflammation and diseases. Thus, the innate immune response needs to be tightly regulated by elaborate mechanisms to control its onset and termination. LPS tolerance is a state of hyporesponsiveness to subsequent LPS challenge and is achieved by monocytic cells after prolonged exposure to LPS. In this report, kinetics of endotoxin-responsive microRNAs expression analysis revealed a unique pattern of gradual increase for miR-146a starting 4 h after LPS stimulation in THP-1 cells and continued up to 35-fold over 24 h. Conversely, TNF-alpha increased up to 4 h and then decreased gradually implicating a negative correlation with miR-146a progression. The characteristic up-regulation of miR-146a toward subsequent LPS challenge in THP-1 cells was studied. Strikingly, microRNA expression analysis during the tolerized state of THP-1 cells showed only miR-146a overexpression suggesting its important role in LPS tolerance. In addition, LPS tolerance was dependent on a LPS-priming dose and associated miR-146a up-regulation. LPS-tolerized cells were observed to regain responsiveness in TNF-alpha production 22 h after LPS removal correlating with a decrease in miR-146a level. Transfection of miR-146a into THP-1 cells mimicked LPS priming, whereas transfection of miR-146a inhibitor largely abolished LPS tolerance. Thus our studies demonstrated that miR-146a is critical for the in vitro monocytic cell-based endotoxin tolerance.

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Cited by

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Authors
Nahid, M. A., Pauley, K. M., Satoh, M., & Chan, E. K. L.
Affiliations
  • University of Florida (US)
  • University of Florida Health (US)
Corresponding author
Chan, Edward K.L.
ORCID
Venue
Journal of Biological Chemistry
Publisher
Elsevier BV
Published
2009-12
Volume
284
Issue
50
Pages
34590-34599
ISSN
0021-9258 (ISSN-L)
DOI
10.1074/jbc.m109.056317
PMC
PMC2787321
OpenAlex
W2101619948
Cited by
423
References
5
Citations by year
2026: 13 · 2025: 14 · 2024: 32 · 2023: 12 · 2022: 17 · 2021: 17 · 2020: 21 · 2019: 17 · 2018: 26 · 2017: 36 · 2016: 25 · 2015: 21 · 2014: 35 · 2013: 42 · 2012: 42
FWCI
13.66
Type
journal article
Language
en
Open access
Licence
Locations
  • Journal of Biological Chemistry (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by-nc)
  • PubMed (publishedVersion)
Funders
  • Lupus Research Institute
  • Lupus Research Alliance
  • National Institutes of Health
  • National Institute of Allergy and Infectious Diseases (R21AI047859, AI47859, R01AI047859)
  • National Institute of Arthritis and Musculoskeletal and Skin Diseases (T32AR007603)
  • National Institute of Dental and Craniofacial Research (T32DE007200)
Topics
  • Life Sciences › Immunology and Microbiology › Immunology › Immune Response and Inflammation
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › MicroRNA in disease regulation
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Inflammasome and immune disorders
Keywords
miR-146a, endotoxin tolerance, lipopolysaccharide, TLR4, TNF-α, innate immune response, microRNA expression, THP-1 cells, monocytic cells, miRNA inhibitors, LPS priming, systemic inflammation
MeSH terms
Animals, Cell Line, Endotoxins, Humans, Immune Tolerance, Immunity, Innate, Lipopolysaccharides, Monocytes, Tumor Necrosis Factor-alpha, Signal Transduction, MicroRNAs, TNF Receptor-Associated Factor 6, Toll-Like Receptor 4, Interleukin-1 Receptor-Associated Kinases, Gene Knockdown Techniques

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