ArticleJournal of immunology (Baltimore, Md. : 1950)2010
SMAD4 is required for development of maximal endotoxin tolerance.
Article in Journal of immunology (Baltimore, Md. : 1950), 2010. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 23 papers.
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The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
23 citing papers in PubMed, 36 citations in OpenAlex.
- The Involvement of MicroRNAs in Innate Immunity and Cystic Fibrosis Lung Disease: A Narrative Review.Current issues in molecular biology · 2026Review
- A polycomb group protein EED epigenetically regulates responses in lipopolysaccharide tolerized macrophages.Epigenetics & chromatin · 2024Article
- Article
- The interplay of DAMPs, TLR4, and proinflammatory cytokines in pulmonary fibrosis.Journal of molecular medicine (Berlin, Germany) · 2021Review
- LPS stimulation during HCV infection induces MMP/TIMP1 imbalance in macrophages.Journal of medical microbiology · 2020Article
- Myalgic encephalomyelitis or chronic fatigue syndrome: how could the illness develop?Metabolic brain disease · 2019Review
- The persistence of low-grade inflammatory monocytes contributes to aggravated atherosclerosis.Nature communications · 2016Article
- SMAD4 is Involved in the Development of Endotoxin Tolerance in Microglia.Cellular and molecular neurobiology · 2016Article
- Computational modeling of cytokine signaling in microglia.Molecular bioSystems · 2015Article
- Pellino-1 Positively Regulates Toll-like Receptor (TLR) 2 and TLR4 Signaling and Is Suppressed upon Induction of Endotoxin Tolerance.The Journal of biological chemistry · 2015Article
- Herb-Partitioned Moxibustion and the miRNAs Related to Crohn's Disease: A Study Based on Rat Models.Evidence-based complementary and alternative medicine : eCAM · 2015Article
- MiR-146b Mediates Endotoxin Tolerance in Human Phagocytes.Mediators of inflammation · 2015Article
- SHIP1 regulates MSC numbers and their osteolineage commitment by limiting induction of the PI3K/Akt/β-catenin/Id2 axis.Stem cells and development · 2014Article
- Role of SHIP1 in bone biology.Annals of the New York Academy of Sciences · 2013Review
- Klf10 inhibits IL-12p40 production in macrophage colony-stimulating factor-induced mouse bone marrow-derived macrophages.European journal of immunology · 2013Article
- Inducible NOS-induced chloride intracellular channel 4 (CLIC4) nuclear translocation regulates macrophage deactivation.Proceedings of the National Academy of Sciences of the United States of America · 2012Article
- Article
- Effects of aging on endotoxin tolerance induced by lipopolysaccharides derived from Porphyromonas gingivalis and Escherichia coli.PloS one · 2012Article
- LPS preconditioning redirects TLR signaling following stroke: TRIF-IRF3 plays a seminal role in mediating tolerance to ischemic injury.Journal of neuroinflammation · 2011Article
- Altered Toll-like receptor 2-mediated endotoxin tolerance is related to diminished interferon beta production.The Journal of biological chemistry · 2011Article
Corrections and comments
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Authors and funding
6 authors at 1 institution in 1 country.
Funding
Abstract
Initial exposure of monocytes/macrophages to LPS induces hyporesponsiveness to a second challenge with LPS, a phenomenon termed LPS tolerance. Molecular mechanisms responsible for endotoxin tolerance are not well defined. We and others have shown that IL-1R-associated kinase (IRAK)-M and SHIP-1 proteins, negative regulators of TLR4 signaling, increase in tolerized cells. TGF-beta1, an anti-inflammatory cytokine, is upregulated following LPS stimulation, mediating its effect through SMAD family proteins. Using a monocytic cell line, THP1, we show that LPS activates endogenous SMAD4, inducing its migration into the nucleus and increasing its expression. Secondary challenge with high dose LPS following initial low-dose LPS exposure does not increase IRAK-M or SHIP1 protein expression in small hairpin (sh)SMAD4 THP-1 cells compared with control shLUC THP1 cells. TNF-alpha concentrations in culture supernatants after second LPS challenge are higher in shSMAD4 THP-1 cells than shLUC THP1 cells, indicating failure to induce maximal tolerance in absence of SMAD4 signaling. Identical results are seen in primary murine macrophages and mouse embryonic fibroblasts, demonstrating the biological significance of our findings. TGF-beta1 treatment does not increase IRAK-M or SHIP1 protein expression in shSMAD4 THP-1 cells, whereas it does so in shLUC THP1 cells, indicating that TGF-beta1 regulates IRAK-M and SHIP1 expression through a SMAD4-dependent pathway. Knockdown of endogenous SHIP1 by shSHIP1 RNA decreases native and inducible IRAK-M protein expression and prevents development of endotoxin tolerance in THP1 cells. We conclude that in THP-1 cells and primary murine cells, SMAD4 signaling is required for maximal induction of endotoxin tolerance via modulation of SHIP1 and IRAK-M.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.