Trial reportJournal of immunology (Baltimore, Md. : 1950)2012
Intracellular heat shock protein-70 negatively regulates TLR4 signaling in the newborn intestinal epithelium.
Trial report in Journal of immunology (Baltimore, Md. : 1950), 2012. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 44 papers.
What it found
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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.
Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.
Who cites it
44 citing papers in PubMed, 89 citations in OpenAlex.
- The single-cell transcriptional landscape of the pediatric cystic fibrosis lung from minimally invasive respiratory specimens.Scientific reports · 2026Article
- HSP-70 and TNF-α as predictors of acute respiratory distress syndrome in children with pneumonia.BMC pediatrics · 2025Article
- Legume lectin phytohemagglutinin reduces transepithelial electrical resistance by counteracting the chaperone function of heat shock protein-70.Journal of nutritional science · 2025Article
- The Effects of HBiomedicines · 2022Article
- Gatekeepers of the Gut: The Roles of Proteasomes at the Gastrointestinal Barrier.Biomolecules · 2021Review
- Surfactant protein A reduces TLR4 and inflammatory cytokine mRNA levels in neonatal mouse ileum.Scientific reports · 2021Article
- Necrotizing Enterocolitis: LPS/TLR4-Induced Crosstalk Between Canonical TGF-β/Wnt/β-Catenin Pathways and PPARγ.Frontiers in pediatrics · 2021Review
- Conserved and Unique Roles of Chaperone-Dependent E3 Ubiquitin Ligase CHIP in Plants.Frontiers in plant science · 2021Review
- A Novel Role for Necroptosis in the Pathogenesis of Necrotizing Enterocolitis.Cellular and molecular gastroenterology and hepatology · 2020Article
- Necrotizing enterocolitis: It's not all in the gut.Experimental biology and medicine (Maywood, N.J.) · 2020Review
- The E3 ubiquitin ligase CHIP in normal cell function and in disease conditions.Annals of the New York Academy of Sciences · 2020Review
- Differential expression of endometrial toll-like receptors (TLRs) and antimicrobial peptides (AMPs) in the buffalo (Bubalus bubalis) with endometritis.Veterinary research communications · 2019Article
- Increased grp78 transcription is correlated to reduced tlr4 transcription in patients surviving sepsis.Clinical and experimental immunology · 2019Article
- Impact of Toll-Like Receptor 4 Signaling in Necrotizing Enterocolitis: The State of the Science.Clinics in perinatology · 2019Review
- New insights into necrotizing enterocolitis: From laboratory observation to personalized prevention and treatment.Journal of pediatric surgery · 2019Review
- Role of intestinal Hsp70 in barrier maintenance: contribution of milk to the induction of Hsp70.2.Pediatric surgery international · 2018Article
- Distinct roles of intracellular heat shock protein 70 in maintaining gastrointestinal homeostasis.American journal of physiology. Gastrointestinal and liver physiology · 2018Article
- Toll-Like Receptor-Mediated Intestinal Inflammatory Imbalance in the Pathogenesis of Necrotizing Enterocolitis.Cellular and molecular gastroenterology and hepatology · 2018Review
- The human milk oligosaccharide 2'-fucosyllactose attenuates the severity of experimental necrotising enterocolitis by enhancing mesenteric perfusion in the neonatal intestine.The British journal of nutrition · 2016Article
- Necrotizing enterocolitis: new insights into pathogenesis and mechanisms.Nature reviews. Gastroenterology & hepatology · 2016Review
Corrections and comments
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Authors and funding
14 authors at 3 institutions in 1 country.
Funding
Abstract
Necrotizing enterocolitis (NEC) is the leading cause of gastrointestinal-related mortality in premature infants, and it develops under conditions of exaggerated TLR4 signaling in the newborn intestinal epithelium. Because NEC does not develop spontaneously, despite the presence of seemingly tonic stimulation of intestinal TLR4, we hypothesized that mechanisms must exist to constrain TLR4 signaling that become diminished during NEC pathogenesis and focused on the intracellular stress response protein and chaperone heat shock protein-70 (Hsp70). We demonstrate that the induction of intracellular Hsp70 in enterocytes dramatically reduced TLR4 signaling, as assessed by LPS-induced NF-κB translocation, cytokine expression, and apoptosis. These findings were confirmed in vivo, using mice that either globally lacked Hsp70 or overexpressed Hsp70 within the intestinal epithelium. TLR4 activation itself significantly increased Hsp70 expression in enterocytes, which provided a mechanism of autoinhibition of TLR4 signaling in enterocytes. In seeking to define the mechanisms involved, intracellular Hsp70-mediated inhibition of TLR4 signaling required both its substrate-binding EEVD domain and association with the cochaperone CHIP, resulting in ubiquitination and proteasomal degradation of TLR4. The expression of Hsp70 in the intestinal epithelium was significantly decreased in murine and human NEC compared with healthy controls, suggesting that loss of Hsp70 protection from TLR4 could lead to NEC. In support of this, intestinal Hsp70 overexpression in mice and pharmacologic upregulation of Hsp70 reversed TLR4-induced cytokines and enterocyte apoptosis, as well as prevented and treated experimental NEC. Thus, a novel TLR4 regulatory pathway exists within the newborn gut involving Hsp70 that may be pharmacologically activated to limit NEC severity.
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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.