ArticleProceedings of the National Academy of Sciences of the United States of America2015
Genetic polymorphism directs IL-6 expression in fibroblasts but not selected other cell types.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 39 papers, 1 of them a synthesis that pooled it.
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Who cites it
39 citing papers in PubMed, 1 synthesis or guideline pooled it, 63 citations in OpenAlex.
- Association of low-grade inflammation caused by gut microbiota disturbances with osteoarthritis: A systematic review.Frontiers in veterinary science · 2022Pooled it
- Biomarkers of inflammation - LBP and TLR- predict progression of knee osteoarthritis in the DOXY clinical trial.Osteoarthritis and cartilage · 2018Trial
- An IL6 variant -174 G-C alters cardiac hypertrophy but not cardiometabolic responses to HFD in mice.npj metabolic health and disease · 2026Article
- Cytokine profiles, genetic polymorphisms, and systemic inflammatory markers in type 1 diabetes patients with COVID-19: IL-18 a predictor of disease severity.Frontiers in immunology · 2026Article
- Pro-Inflammatory Signaling in Dermal Fibroblasts: A Possible Role of Different Botulinum Toxin Formulations on IL-6 Expression.Journal of cosmetic dermatology · 2026Article
- PCBP2 Regulates p16Aging cell · 2025Article
- Pro-Inflammatory Properties of Salivary Gland-Derived Fibroblasts-Implications in Sjögren's Disease.Cells · 2025Article
- The Regulatory Role of CTCF in IL6 Gene Transcription Assessed in Breast Cancer Cell Lines.Pharmaceuticals (Basel, Switzerland) · 2025Article
- Associations between IL-1β, IL-6, and TNFα polymorphisms and longitudinal trajectories of cognitive function in non-demented older adults.Brain, behavior, & immunity - health · 2024Article
- Association between interleukin-6-174G/C gene polymorphism and asthma severity: exploring the role of total serum IgE, blood eosinophils, and FeNO as markers of type 2 inflammation.Allergy, asthma, and clinical immunology : official journal of the Canadian Society of Allergy and Clinical Immunology · 2024Article
- Article
- The Role of Genetics and Epigenetic Regulation in the Pathogenesis of Osteoarthritis.International journal of molecular sciences · 2023Review
- SATB2, coordinated with CUX1, regulates IL-1β-induced senescence-like phenotype in endothelial cells by fine-tuning the atherosclerosis-associated p16Aging cell · 2023Article
- An interleukin 6-based genetic risk score strengthened with interleukin 10 polymorphisms associated with long-term kidney allograft outcomes.American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons · 2022Article
- Post-GWAS functional analysis identifies CUX1 as a regulator of p16Nature aging · 2022Article
- Coupling high-throughput mapping with proteomics analysis delineates cis-regulatory elements at high resolution.Nucleic acids research · 2022Article
- Essential immune functions of fibroblasts in innate host defense.Frontiers in immunology · 2022Review
- Article
- Donor genetic variants in interleukin-6 and interleukin-6 receptor associate with biopsy-proven rejection following kidney transplantation.Scientific reports · 2021Article
- Post-GWAS functional studies reveal an RA-associated CD40-induced NF-kB signal transduction and transcriptional regulation network targeted by class II HDAC inhibitors.Human molecular genetics · 2021Article
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5 authors at 2 institutions in 1 country.
Funding
Abstract
Interleukin (IL)-6 blockade is an effective treatment for rheumatoid arthritis (RA), and synovial fibroblasts are a major IL-6 producer in the inflamed joint. We found that human RA and osteoarthritis (OA) synovial fibroblasts derived from independent donors reproducibly segregated into low, medium, and high IL-6 producers, independent of stimulus, cell passage, or disease state. IL-6 expression pattern correlated strongly with total mRNA expression, not mRNA stability, suggesting transcriptional rather than posttranscriptional regulation. High-fibroblast IL-6 expression was significantly associated with the IL-6 proximal promoter single nucleotide polymorphism (SNP) rs1800795 minor allele (CC) genotype. In contrast, no association between this SNP and IL-6 production was detected in CD14(+) monocytes, another major producer of synovial IL-6. Luciferase expression assays confirmed that this SNP was associated with differential IL-6 expression in fibroblasts. To date, several association studies examining rs1800795 allele frequency and disease risk have reported seemingly conflicting results ranging from no association to association with either the major or minor allele across a spectrum of conditions, including cancer and autoimmune, cardiovascular, infectious, and metabolic diseases. This study points to a prominent contribution from promoter genetic variation in fibroblast IL-6 regulation, but not in other IL-6-producing cell types. We propose that some of the heterogeneity in these clinical studies likely reflects the cellular source of IL-6 in specific diseases, much of which may be produced by nonhematopoietic cells. These results highlight that functional analysis of disease-associated SNPs on gene expression and pathologic processes must consider variation in diverse cell types.
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