Epigenetic Regulation of Interleukin 6 by Histone Acetylation in Macrophages and Its Role in Paraquat-Induced Pulmonary Fibrosis
Open accessAbstract
Overexpression of IL-6 has been proposed to contribute to pulmonary fibrosis and other fibrotic diseases. However, the regulatory mechanisms as well as the role of IL-6 in fibrosis remain poorly understood. Epigenetics refers to alterations of gene expression without changes in the DNA sequence. Alternation of chromatin accessibility by histone acetylation acts as a critical epigenetic mechanism to regulate a variety of gene transcription. The goal of this study was to determine the impact of IL-6 in paraquat induced pulmonary fibrosis and to explore whether the epigenetic regulations may play a role in transcriptional regulation of IL-6. In paraquat treated lungs and macrophages, we found that the mRNA and protein expression of IL-6 was robustly increased in a time-dependent and a dose-dependent manner. Our data demonstrated that paraquat induced IL-6 expression in macrophages plays a central role in pulmonary fibrosis through enhanced epithelial to mesenchymal transition (EMT). IL-6 expression and its role to enhance paraquat induced pulmonary fibrosis were increased by HDAC inhibition and prevented by HAT inhibition. In addition, the ability of CRISPR-ON transcription activation system (CRISPR-ON) to promote transcription of IL-6 was enhanced by HAT inhibitor and blocked by HDAC inhibitor. We further showed that ChIP experiments revealed that HDAC inhibitors increase histones activation marks H3K4me3 and H3K9ac at IL-6 promoter regions. In conclusion, IL-6 functioning through EMT in paraquat induced pulmonary fibrosis was regulated dynamically by HDAC and HAT both in vitro and in vivo via epigenetically regulating chromatin accessibility.
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IL-6 transcription is induced by a variety of stimuli, such as Toll-like receptor ligands, IL-1, TNFα, reactive oxygen species and zinc, and also depends on epigenetic regulation.
“IL-6 transcription is induced by a variety of stimuli, such as Toll-like receptor (TLR) ligands, IL-1, TNFα, reactive oxygen species (ROS) and zinc (Zn) and also depends on epigenetic regulation (33, 82, 84–86).”
From IL-6 in inflammation, autoimmunity and cancer (2021) · cites this paper as [86]
The Discussion reports that histone modifications at the IL-6 promoter regulate its transcriptional activity, supporting the epigenetic-regulation part of the sentence. The paper does not establish the listed TLR ligands, IL-1, TNFα, ROS, and zinc as inducers of IL-6 transcription. No page numbers are available in our copy. (LLM, conf=0.86)
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ResultMouse model of paraquat-poisoned lungs and its gene expression profile.
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The metabolic signature of macrophage responses
Viola, A., Munari, F., Sánchez-Rodríguez, R., Scolaro, T., & Castegna, A. (2019) · Frontiers in Immunology · doi:10.3389/fimmu.2019.01462 · Cited by 2,021 · see citing works
“Finally, M2d macrophages, also known as tumor-associated macrophages (TAMs), are induced by TLR ligands and A2 adenosine receptor (A2R) agonists, or by IL-6; they secrete high levels of IL-10, TGF-β, and VEGF and low IL12, TNF-α, and IL-1β, and contribute to tumor angiogenesis, growth and metastasis (25).”
BackgroundInfluentialIL-6 in inflammation, autoimmunity and cancer
Hirano, T. (2021) · International Immunology · doi:10.1093/intimm/dxaa078 · Cited by 1,453 · see citing works
“IL-6 transcription is induced by a variety of stimuli, such as Toll-like receptor (TLR) ligands, IL-1, TNF α , reactive oxygen species (ROS) and zinc (Zn) and also depends on epigenetic regulation (33, 82, 84–86).”
BackgroundPleiotropy and specificity: insights from the interleukin 6 family of cytokines
Murakami, M., Kamimura, D., & Hirano, T. (2019) · Immunity · doi:10.1016/j.immuni.2019.03.027 · Cited by 533 · see citing works
Williams, N. C., & O'Neill, L. A. J. (2018) · Frontiers in Immunology · doi:10.3389/fimmu.2018.00141 · Cited by 569 · see citing works
“IL-6 and IL-10 production are both regulated on histone and non-histone protein acetylation, respectively (78, 79).”
BackgroundKrebs cycle Reborn in macrophage immunometabolism
Ryan, D. G., & O'Neill, L. A. J. (2020) · Annual Review of Immunology · doi:10.1146/annurev-immunol-081619-104850 · Cited by 444 · see citing works
“Inhibition of these demethylases subsequently increases the levels of H3K4me3, a marker of active gene transcription, at the promoters of the proinflammatory cytokines TNF and IL-6, boosting their production upon restimulation with LPS (46).”
BackgroundInfluentialMetabolic Modulation in Macrophage Effector Function
Diskin, C., & Pålsson‐McDermott, E. M. (2018) · Frontiers in Immunology · doi:10.3389/fimmu.2018.00270 · Cited by 292 · see citing works
“These epigenetic changes could be of great importance in the context of inflammation; for example, IL-6 expression has been shown to be regulated by histone acetylation in macrophages (63).”
BackgroundTricarboxylic Acid (TCA) Cycle Intermediates: Regulators of Immune Responses
Choi, I., Son, H., & Baek, J.-H. (2021) · Life · doi:10.3390/life11010069 · Cited by 244 · see citing works
“expression of interleukin (IL)-6 in virus-infected [22] and paraquat (PQ)-treated [23] mac-”
BackgroundChromatin accessibility: biological functions, molecular mechanisms and therapeutic application
Chen, Y., Liang, R., Li, Y., Jiang, L., Ma, D., Luo, Q., & Song, G. (2024) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-024-02030-9 · Cited by 174 · see citing works
Krebs cycle rewired for macrophage and dendritic cell effector functions
Ryan, D. G., & O'Neill, L. A. J. (2017) · FEBS Letters · doi:10.1002/1873-3468.12744 · Cited by 150 · see citing works
The JAK/STAT Pathway in Skeletal Muscle Pathophysiology
Moresi, V., Adamo, S., & Berghella, L. (2019) · Frontiers in Physiology · doi:10.3389/fphys.2019.00500 · Cited by 141 · see citing works
Daskalaki, M., Tsatsanis, C., & Kampranis, S. C. (2018) · Journal of Cellular Physiology · doi:10.1002/jcp.26497 · Cited by 137 · see citing works
“paraquat-activated murine macrophages (Hu et al., 2016).”
BackgroundHDAC inhibitors as antifibrotic drugs in cardiac and pulmonary fibrosis
Lyu, X., Hu, M., Peng, J., Zhang, X.-Y., & Sanders, Y. (2019) · Therapeutic Advances in Chronic Disease · doi:10.1177/2040622319862697 · Cited by 121 · see citing works
Wang, Y.-C., Wu, Y.-S., Hung, C.-Y., Wang, S., Young, M.-J., Hsu, T., & Hung, J. (2018) · Nature Communications · doi:10.1038/s41467-018-06178-1 · Cited by 106 · see citing works
Liu, L.-X., Sun, Q.-Z., Davis, F. G., Mao, J.-H., Zhao, H.-L., & Ma, D.-Q. (2022) · Burns & Trauma · doi:10.1093/burnst/tkac011 · Cited by 90 · see citing works
“Enhancement of IL-6 was shown to regulate paraquat-induced pulmonary EMT [85].”
InfluentialNew insights into the genetics and epigenetics of systemic sclerosis
Angiolilli, C., Marut, W., Kroef, M., Chouri, E., Reedquist, K., & Radstake, T. (2018) · Nature Reviews Rheumatology · doi:10.1038/s41584-018-0099-0 · Cited by 84 · see citing works
Metabolic Routes in Inflammation: The Citrate Pathway and its Potential as Therapeutic Target
Infantino, V., Pierri, C. L., & Iacobazzi, V. (2018) · Current Medicinal Chemistry · doi:10.2174/0929867325666180510124558 · Cited by 96 · see citing works
Reactive Oxygen Species Drive Epigenetic Changes in Radiation-Induced Fibrosis
Shrishrimal, S., Kosmacek, E. A., & Oberley‐Deegan, R. E. (2019) · Oxidative Medicine and Cellular Longevity · doi:10.1155/2019/4278658 · Cited by 91 · see citing works
Ahmad, S., Manzoor, S., Siddiqui, S., Mariappan, N., Zafar, I., Ahmad, A., & Ahmad, A. M. (2021) · Seminars in Cancer Biology · doi:10.1016/j.semcancer.2021.01.003 · Cited by 89 · see citing works
“In paraquat induced pulmonary fibrosis model, imbalance in HATs and HDAC has been shown to regulate IL-6 expression [232].”
BackgroundMacrophage Plasticity in Reproduction and Environmental Influences on Their Function
Chambers, M., Rees, A., Cronin, J., Nair, M., Jones, N., & Thornton, C. (2021) · Frontiers in Immunology · doi:10.3389/fimmu.2020.607328 · Cited by 71 · see citing works
“These metabolites are involved in the regulation of inflammatory gene expression (31, 32).”
BackgroundKainthola, A., Haritwal, T., Tiwari, M., Gupta, N., Parvez, S., Tiwari, M., Prakash, H., & Agrawala, P. K. (2017) · Frontiers in Immunology · doi:10.3389/fimmu.2017.00506 · Cited by 77 · see citing works
“(123) have shown epigenetic regulation of IL-6 by changing HAT and HDAC dyanamics in a paraquat-induced pulmonary fibrosis model.”
BackgroundMultistability in Macrophage Activation Pathways and Metabolic Implications
Geiß, C., Salas, E., Guevara-Coto, J. A., Régnier‐Vigouroux, A., & Mora-Rodríguez, R. A. (2022) · Cells · doi:10.3390/cells11030404 · Cited by 76 · see citing works
Pharmacological targets of metabolism in disease: Opportunities from macrophages
Castegna, A., Gissi, R., Menga, A., Montopoli, M., Favia, M., Viola, A., & Canton, M. (2020) · Pharmacology & Therapeutics · doi:10.1016/j.pharmthera.2020.107521 · Cited by 75 · see citing works
IL-6 family cytokines in respiratory health and disease
Dawson, R., Jenkins, B. J., & Saad, M. I. (2021) · Cytokine · doi:10.1016/j.cyto.2021.155520 · Cited by 64 · see citing works
Inhibition of airway remodeling and inflammatory response by Icariin in asthma
Hu, L.-L., Li, L.-L., Zhang, H.-Y., Li, Q.-P., Jiang, S., Qiu, J., Sun, J., & Dong, J.-C. (2019) · BMC Complementary and Alternative Medicine · doi:10.1186/s12906-019-2743-x · Cited by 54 · see citing works
“following process were consistent with our previous experiment [38].”
MethodResultSelf-citationThe epigenetic hallmarks of immune cells in cancer
Yu, J. H., Xiao, C., Fan, T. T., Deng, Z., Wang, D., Cai, W., Li, J., Liao, T., Li, C., & He, J. (2025) · Molecular Cancer · doi:10.1186/s12943-025-02255-4 · Cited by 49 · see citing works
“For example, TSA treatment blocks HDAC9-mediated deacetylation on Foxp3 genes to boost Treg cells [341], while VPA promotes the distribution of H3K9ac and H3K4me3 over Il6 promoter regions to enhance M2 polarization of macrophages [342].”
Al-Roub, A., Madhoun, A. S. A., Akhter, N., Thomas, R., Miranda, L., JACOB, T. K., Al‐Ozairi, E., Al‐Mulla, F., Sindhu, S. T. A. K., & Ahmad, R. (2021) · Cells · doi:10.3390/cells10113228 · Cited by 62 · see citing works
“In response to stimuli, histone acetylation mediates epigenetic modification at IL-6 promoter and induces transcription [42].”
BackgroundManagement of epigenomic networks entailed in coronavirus infections and COVID-19
Baba, R. E., & Herbein, G. (2020) · Clinical Epigenetics · doi:10.1186/s13148-020-00912-7 · Cited by 49 · see citing works
“HAT Anacardic acid, MG149, C646 Suppressed IL-6 levels [60, 61].”
BackgroundGuo, Z., Wang, L., Liu, H., & Xie, Y. (2022) · Cells · doi:10.3390/cells11244072 · Cited by 51 · see citing works
“It has been reported that histone acetylation is involved in the regulation of the inflammatory gene transcription of macrophages [101,102].”
BackgroundBeacon, T. H., Su, R.-C., Lakowski, T. M., Delcuve, G., & Davie, J. (2020) · IUBMB Life - A Journal of the International Union of Biochemistry and Molecular Biology · doi:10.1002/iub.2379 · Cited by 45 · see citing works
“As is typical of expressed genes, the IL-6 promoter region is associated with H3K4me3 and H3K9ac, Dot1l-mediated H3K79me2/3, and is regulated by dynamic histone acetylation.(205,206) The IL-6 promoter is regulated by NF-κB, C/EBP, IRF-1, Sp1, and AP-1 transcription factors.”
BackgroundInflammation driven metabolic regulation and adaptation in macrophages
Gupta, S., & Sarangi, P. P. (2022) · Clinical Immunology · doi:10.1016/j.clim.2022.109216 · Cited by 45 · see citing works
Zhang, Y., Li, Y.-S., Li, J., Li, B., Chong, Y.-Z., Zheng, G.-Y., Sun, S.-F., & Feng, F. (2019) · International Immunopharmacology · doi:10.1016/j.intimp.2018.11.054 · Cited by 43 · see citing works
Epigenetic remodeling of the immune landscape in cancer: therapeutic hurdles and opportunities
Tien, F., Lu, H., Lin, S., & Tsai, H.-C. (2023) · Journal of Biomedical Science · doi:10.1186/s12929-022-00893-0 · Cited by 50 · see citing works
Postinfectious Epigenetic Immune Modifications — A Double-Edged Sword
DiNardo, A. R., Netea, M. G., & Musher, D. M. (2021) · New England Journal of Medicine · doi:10.1056/nejmra2028358 · Cited by 58 · see citing works
Epigenetic Modifications in Tumor-Associated Macrophages: A New Perspective for an Old Foe
Niu, Y., Chen, J., & Qiao, Y. (2022) · Frontiers in Immunology · doi:10.3389/fimmu.2022.836223 · Cited by 48 · see citing works
“reported that sodium valproate, a widely used HDAC inhibitor, increased histone activation marks H3K4me3 and H3K9ac at Il6 promoter regions in a murine paraquat-induced pulmonary fibrosis model (107).”
BackgroundTian, Y., Shi, H., Zhang, D., Wang, C., Zhao, F., Li, L., Xu, Z., Jiang, J., & Li, J. (2023) · Journal of Controlled Release · doi:10.1016/j.jconrel.2023.10.018 · Cited by 34 · see citing works
Okano, T., Imai, K., Naruto, T., Okada, S., Yamashita, M., Yeh, T.-W., Ono, S., Tanaka, K., Okamoto, K., Tanita, K., et al. (2020) · Journal of Clinical Immunology · doi:10.1007/s10875-020-00798-3 · Cited by 31 · see citing works
Tricarboxylic acid cycle metabolites: new players in macrophage
Yang, Y., Cui, B.-B., Li, J., Shan, J.-J., Xu, J., Zhang, C.-Y., Wei, X.-T., Zhu, R.-R., & Wang, J. (2024) · Inflammation Research · doi:10.1007/s00011-024-01853-0 · Cited by 32 · see citing works
“Histone acetyltransferases catalyze the transfer of acetyl groups from acetyl-CoA to histones, while histone deacety-lases remove them [22, 23].”
Mesenchymal cells in the Lung: Evolving concepts and their role in fibrosis
Ligresti, G., Raslan, A., Hong, J., Caporarello, N., Confalonieri, M., & Huang, S. K. (2023) · Gene · doi:10.1016/j.gene.2022.147142 · Cited by 34 · see citing works
Understanding the epigenetic mechanisms in SARS CoV-2 infection and potential therapeutic approaches
Bhat, S., Rishi, P., & Chadha, V. (2022) · Virus Research · doi:10.1016/j.virusres.2022.198853 · Cited by 27 · see citing works
Sun, X., Tian, Q., Wang, L.-Y., Xue, M., & Zhong, G. (2017) · Microbes and infection · doi:10.1016/j.micinf.2017.08.007 · Cited by 26 · see citing works
Systematic Review of Multi-Omics Approaches to Investigate Toxicological Effects in Macrophages
Karkossa, I., Raps, S., von Bergen�, M., & Schubert, K. A. (2020) · International Journal of Molecular Sciences · doi:10.3390/ijms21249371 · Cited by 29 · see citing works
“, NMs [55,171], fungicides [172], herbicides [173], insecticides [174], and plasticizers [175] based on single parameters like toxicological endpoints, real-time PCR, or Western blotting before.”
BackgroundHistone deacetylase 5 regulates interleukin 6 secretion and insulin action in skeletal muscle
Klymenko, O., Brecklinghaus, T., Dille, M., Springer, C., de Wendt, C., Altenhofen, D., Binsch, C., Knebel, B., Scheller, J., Hardt, C., et al. (2020) · Molecular Metabolism · doi:10.1016/j.molmet.2020.101062 · Cited by 25 · see citing works
“Consistent with our findings, a recent study reported increased AcH3K9 and H3K4me3 histone activation markers in the Il6 promoter region in macrophages after treatment with Scriptaid, an inhibitor of class IIa HDAC coerepressor complex formation [39].”
BackgroundHu, L.-L., Liu, F., Li, L.-L., Zhang, L., Yan, C., Li, Q.-P., Qiu, J., Dong, J.-C., Sun, J., & Zhang, H.-Y. (2020) · Experimental and Therapeutic Medicine · doi:10.3892/etm.2020.8702 · Cited by 23 · see citing works
“Western blotting was subsequently performed as previously described (34).”
Self-citationFan, H., Huang, H.-J., Hu, L., Zhu, W., Yu, Y.-F., Lou, J., Hu, L.-L., & Chen, F. (2018) · Toxicology Letters · doi:10.1016/j.toxlet.2018.04.030 · Cited by 23 · see citing works
Self-citationPhytonutrients and their neuroprotective role in brain disorders
Adhikary, K., Ganguly, K., Sarkar, R., Abubakar, M., Banerjee, P., & Karak, P. (2025) · Frontiers in Molecular Biosciences · doi:10.3389/fmolb.2025.1607330 · Cited by 22 · see citing works
The Killer’s Web: Interconnection between Inflammation, Epigenetics and Nutrition in Cancer
Mecca, M., Picerno, S., & Cortellino, S. (2024) · International Journal of Molecular Sciences · doi:10.3390/ijms25052750 · Cited by 23 · see citing works
“In paraquat-induced pulmonary fibrosis, elevated IL-6 expression depends on acetylation of H3K9ac in the IL6 promoter region [135].”
BackgroundYu, Y.-J., Gao, Z.-S., Lou, J., Mao, Z.-S., Li, K., Chu, C., Hu, L., Li, Z., Deng, C., Fan, H., et al. (2020) · Frontiers in Physiology · doi:10.3389/fphys.2020.00065 · Cited by 21
Self-citationHu, L.-L., Li, L.-L., Yan, C., Cao, Y.-X., Duan, X.-H., & Sun, J. (2023) · Oxidative Medicine and Cellular Longevity · doi:10.1155/2023/4144138 · Cited by 20
“The process detects mRNA expression by qPCR agrees with our earlier experiments [19].”
ResultSelf-citationEffects of paraquat on IL-6 and TNF-α in macrophages
Huang, J., Ning, N., & Zhang, W. (2018) · Experimental and Therapeutic Medicine · doi:10.3892/etm.2018.7099 · Cited by 20
“The invasion of PQ causes significant overexpression of pro-inflammatory mediators, which shows multiple organ dysfunction and failure, resulting in death in patients (19).”
BackgroundLiu, Y., Wang, X., Jin, C., Qiao, J., Wang, C., Jiang, L., Yu, S., Pan, D., Zhao, D., Wang, S., et al. (2024) · Phytomedicine · doi:10.1016/j.phymed.2024.155650 · Cited by 17 · see citing works
Zhan, Y., Guo, Z.-K., Zheng, F.-L., Zhang, Z., Li, K., Wang, Q., Wang, L., Cai, Z.-P., Chen, N.-Z., Wu, S.-Y., et al. (2020) · Environmental Toxicology · doi:10.1002/tox.23001 · Cited by 18
“A large number of studies have shown that PQmay be involved in the development of Parkinson's disease (PD).(1,2) In our previous study, we found that PQ could cause nerve cell damage and reduce the expression of miR-17-5p in neuro-2a cells.”
BackgroundSelf-citationHistone hyperacetylation mediates enhanced IL‐1β production in LPS/IFN‐γ‐stimulated macrophages
Dong, Z., Li, R., Xu, L., Xin, K., Xu, Y., Shi, H., Sun, A., & Ge, J. (2020) · Immunology · doi:10.1111/imm.13183 · Cited by 21 · see citing works
CRISPR Editing in Biological and Biomedical Investigation
Zhang, H., & McCarty, N. (2017) · Journal of Cellular Biochemistry · doi:10.1002/jcb.26111 · Cited by 8 · see citing works
“This study provides an extensive set of systems to generate more reliable tools for improved activation, especially for the highly repressed genes, although most uses of the CRISPRa method have thus far been limited to preliminary function studies [Hu et al., 2016; Guo et al., 2017; Koirala et al., 2017].”
MethodHua, H.-S., Wen, H.-C., Lee, H.-S., Weng, C.-M., Yuliani, F. S., Kuo, H.-P., Chen, B.-C., & Lin, C.-H. (2023) · Journal of Biomedical Sciences · doi:10.1186/s12929-023-00931-5 · Cited by 17 · see citing works
“Histone H3 acetylation was reported to contribute to the overexpression of profibrotic cytokine interleukin-6 in paraquatinduced pulmonary fibrosis [21].”
BackgroundYuan, J.-L., Mo, Y., Zhang, Y.-B., Zhang, Y., & Zhang, Q.-W. (2022) · Nanotoxicology · doi:10.1080/17435390.2022.2142169 · Cited by 17
“On the other hand, valproate sodium salt, a Class I HDAC Inhibitor, was reported to resist EMT development in paraquat-induced pulmonary fibrosis by increasing H3K9ac levels in the IL-6 promoter (Hu et al. 2016).”
BackgroundHigh-Fat Diet Related Lung Fibrosis-Epigenetic Regulation Matters
Yang, J.-T., Liang, C.-X., Liu, L., Wang, L., & Yu, G.-Y. (2023) · Biomolecules · doi:10.3390/biom13030558 · Cited by 16 · see citing works
“This evidence suggested that histone modification is crucial for HFD mediated EMT in lung fibrosis progression.”
BackgroundInfluentialEvans, H. M., Schultz, D. F., Boiman, A. J., McKell, M. C., Qualls, J. E., & Deepe, G. S. (2021) · mBio · doi:10.1128/mbio.02710-21 · Cited by 19 · see citing works
Wu, M., Zhou, C.-Y., Li, M., Yu, H.-B., Zhao, D.-K., Xue, W., Qin, L., & Peng, A. (2020) · International Immunopharmacology · doi:10.1016/j.intimp.2020.106698 · Cited by 16
Pucci, S., Greggi, C., Polidoro, C., Piro, M., Celi, M., Feola, M., Gasbarra, E., Iundusi, R., Mastrangeli, F., Novelli, G., et al. (2019) · Journal of Translational Medicine · doi:10.1186/s12967-019-1868-5 · Cited by 16 · see citing works
“Since IL6 expression is epigenetically regulated and no data are available on muscle acetylation pattern in OA an OP condition, we observed H4 acetylation state in the same tissues [28, 29].”
BackgroundSun, P., Zhang, S., Maksim, S., Yao, Y., Liu, H., & Du, J. (2019) · Current Topics in Medicinal Chemistry · doi:10.2174/1568026619666190619143706 · Cited by 24 · see citing works
The Methyltransferase Smyd1 Mediates LPS-Triggered Up-Regulation of IL-6 in Endothelial Cells
Shamloul, A., Steinemann, G., Roos, K., Liem, C. H., Bernd, J., Braun, T., Zakrzewicz, A., & Berkholz, J. (2021) · Cells · doi:10.3390/cells10123515 · Cited by 14 · see citing works
“(5) Histone modifications are also known to be involved in IL-6 gene expression [32,34,54,55].”
BackgroundEpigenetic Control of Alveolar Macrophages: Impact on Lung Health and Disease
Parajuli, N., Subedi, K., Solone, X. K., Jiang, A., Zhou, L., & Mi, Q. (2025) · Cells · doi:10.3390/cells14090640 · Cited by 13 · see citing works
“Conversely, histone acetylation marks, such as H3K4me3 and H3K9ac, are enriched in fibrotic macrophages [103].”
SMARCB1 Acts as a Quiescent Gatekeeper for Cell Cycle and Immune Response in Human Cells
Choi, S. K., Kim, M. J., & You, J. (2020) · International Journal of Molecular Sciences · doi:10.3390/ijms21113969 · Cited by 13
“On the other hand, IL6 is known to be regulated by epigenetic mechanisms, such as DNA methylation and histone modifications, and the active transcription of IL6 is usually correlated with DNA hypomethylation and active histone modifications in several contexts [45,46].”
BackgroundHAT/HDAC: The epigenetic regulators of inflammatory gene expression (Review)
Swaroop, S., Batabyal, A., & Bhattacharjee, A. (2021) · International Journal of Epigenetics · doi:10.3892/ije.2021.5 · Cited by 12 · see citing works
“ON transcription activation system in the presence of a HAT inhibitor and increased transcription in presence of an HDACi has been observed (33).”
Lujan, H., Romer, E. J., Salisbury, R. L., Hussain, S. M., & Sayes, C. M. (2020) · Toxicological Sciences · doi:10.1093/toxsci/kfaa028 · Cited by 20 · see citing works
A new sight for paraquat poisoning from immunology
Wu, Q., Xu, Q.-L., Jian, X.-D., Wang, H.-X., He, X.-D., Gao, B.-J., Wang, K., & Kan, B.-T. (2018) · Immunopharmacology and immunotoxicology · doi:10.1080/08923973.2018.1490319 · Cited by 11
“There is a close relationship between fibrosis and the immune response [5], especially as it relates to macrophages, during fibrosis [6].”
BackgroundPoly (ADP-ribose) Polymerase-1 modulations in the genesis of thrombosis
Safdar, R., Mishra, A., Shah, G. M., & Ashraf, M. Z. (2024) · Journal of Thrombosis and Thrombolysis · doi:10.1007/s11239-024-02974-3 · Cited by 10 · see citing works
“Histone acetyltransferases (HATs) such as p300 stimulate pro-inflammatory IL-6 expression [89] under inflammatory circumstances and catalyze acetylation of the Nox5 gene promoter [90].”
Velázquez-Enríquez, J. M., Reyes-Avendaño, I., Santos-Álvarez, J. C., Reyes-Jiménez, E., Vásquez-Garzón, V. R., & Baltiérrez‐Hoyos, R. (2023) · Advances in respiratory medicine · doi:10.3390/arm91050032 · Cited by 9 · see citing works
“The IL6 gene encodes the protein interleukin-6 (IL-6), a cytokine with multiple functions associated with immune responses and inflammation; therefore, it has been closely related to the pathology of different chronic inflammatory and autoimmune diseases [93,94].”
BackgroundVenosa, A., Smith, L., Gow, A., Zarbl, H., Laskin, J., & Laskin, D. (2021) · Toxicology and Applied Pharmacology · doi:10.1016/j.taap.2021.115569 · Cited by 10 · see citing works
Tissue Fibrosis Decoded via Cellular Senescence: Mechanisms, Treatments, and Emerging Technologies
Cai, W., Zhang, H., Li, Z., Cai, M., Yu, S.-W., Chen, P., & Song, X. (2025) · Aging and Disease · doi:10.14336/ad.2025.0503 · Cited by 8
“Histone acetylation can directly regulate the gene expression of inflammatory cytokines such as IL-6 and fibronectin, thus affecting the progression of pulmonary fibrosis [149, 150].”
Chokeberry reduces inflammation in human preadipocytes
Brunelle, D. C., Larson, K., Bundy, A. N., Roemmich, J. N., Warne, D. K., & Redvers, N. (2023) · Journal of Functional Foods · doi:10.1016/j.jff.2023.105947 · Cited by 8 · see citing works
“Research using Chromatin Immunoprecipitation (ChIP) has been used to determine acetylation of histone H3 specific to the IL-6 promoter (Wada et al., 2014; Hu et al., 2017; Zhang et al., 2015).”
BackgroundMethodInfluentialThe role of immunomodulatory metabolites in shaping the inflammatory response of macrophages
Park, D., Lim, G., Yoon, S., Yi, H., & Choi, D. W. (2022) · BMB Reports · doi:10.5483/bmbrep.2022.55.11.128 · Cited by 12 · see citing works
“produce acetyl-CoA, a key regulatory signal that links metabolism with the epigenetic regulations required for proinflammatory gene expression, such as IL-6 production (89-91).”
BackgroundLi, P.-S., Wang, G., Peng, Z., Zhang, L., Yang, F., Wei, Y., Pan, M., Zang, H., & Zhou, M. (2025) · Journal of Inflammation Research · doi:10.2147/jir.s560635 · Cited by 6 · see citing works
Epigenetic regulation of immune cells in central nervous system: from steady state to pathology
Zhao, L., Schepp, C. L., Iskandar, M., Tao, Y., & Dey, M. (2025) · Neurochemistry International · doi:10.1016/j.neuint.2025.106005 · Cited by 6 · see citing works
Yu, Y.-J., Chu, C., Wang, K., Li, Y., Mao, Z., Hu, L., Wang, J., Yu, Y.-F., Sun, H., & Chen, F. (2024) · Respiratory Research · doi:10.1186/s12931-024-02832-z · Cited by 6 · see citing works
“Current knowledge attributes these PQ-induced pulmonary injuries to redox cycle disruption [3], induction of cellular apoptosis [25], and subsequent initiation of inflammatory responses [13].”
BackgroundSelf-citationMetabolic Adaptations and Functional Activity of Macrophages in Homeostasis and Inflammation
Yurakova, T. R., Gorshkova, E. A., Nosenko, M. A., & Drutskaya, M. S. (2024) · Biochemistry (Moscow) · doi:10.1134/s0006297924050043 · Cited by 7 · see citing works
Nutraceuticals as potential therapeutics for vesicant-induced pulmonary fibrosis
Businaro, R., Maggi, E., Armeli, F., Murray, A., & Laskin, D. (2020) · Annals of the New York Academy of Sciences · doi:10.1111/nyas.14442 · Cited by 6 · see citing works
Kim, H., Kang, L., & Park, S. (2025) · Stem Cell Research & Therapy · doi:10.1186/s13287-025-04719-2 · Cited by 5 · see citing works
Du, Q.-Y., Wu, X., An, L., Zhou, R.-F., Xiao, X., Wu, C., Wang, F., & Yang, H. (2022) · Evidence-Based Complementary and Alternative Medicine · doi:10.1155/2022/4933255 · Cited by 5 · see citing works
Prevention of bleomycin-induced pulmonary fibrosis by vaccination with the Tocilizumab mimotope
Guo, J., Yang, L., Song, H., & Bai, L. (2024) · Human Vaccines & Immunotherapeutics · doi:10.1080/21645515.2024.2319965 · Cited by 5 · see citing works
Paraquat modulates immunological function in bone marrow-derived macrophages.
Srinontong, P., Wandee, J., & Aengwanich, W. (2021) · Acta Veterinaria Hungarica · doi:10.21203/rs.3.rs-407029/v1 · Cited by 4
“The increase of IL-6 expression of BMDM after incubating with PQ in this study is similar to the report of Hu et al. (2017) who found that during PQ exposure, PQ induced alveolar macrophages to produce IL-6 and caused pulmonary brosis.”
ResultEffect of WISP1 on paraquat-induced EMT
Liu, J., Lv, S., Ma, W., Yang, D., & Zhang, X. (2023) · Toxicology in Vitro · doi:10.1016/j.tiv.2023.105693 · Cited by 3 · see citing works
Kiran, G. S., Kumar, P. K., Mitra, P., Kumar, K., Goyal, T., Sharma, S., Rana, S., & Sharma, P. (2023) · International Archives of Occupational and Environmental Health · doi:10.1007/s00420-023-02004-4 · Cited by 4 · see citing works
“(Hu et al. 2017).”
BackgroundBistability in macrophage polarization and metabolic implications
Geiß, C., Salas, E., Guevara-Coto, J., Régnier-Vigouroux, A., & Mora-Rodríguez, R. (2021) · doi:10.20944/preprints202112.0416.v1 · Cited by 2
“Particularly, in M1 macrophages, the expression of proteins, like NF-κB, IL-6, and IL-10 is modified by acetylation [121,122].”
BackgroundZeng, X.-X., Hu, J.-L., Yan, M., Xie, C., Xu, W.-G., Hu, Q., Feng, J.-X., Gu, Z.-C., & Fu, Y. (2021) · Aging · doi:10.18632/aging.203570 · Cited by 2 · see citing works
“PQ intoxication leads to health damage in human health and causes multiple serious diseases, such as severe pulmonary inflammation, edema, and pulmonary fibrosis, which have high mortality rate and lack effective therapeutic strategies [3, 4].”
BackgroundElshamy, G., El-Bassossy, H., Elshazly, S. M., & Elkomy, N. M. I. M. (2025) · Journal of Natural Medicines · doi:10.1007/s11418-025-01960-0 · Cited by 1 · see citing works
Global Analysis of the Lysine Acetylome in Macrophages from Salt-sensitive Hypertensive Rats
Xie, D., Dong, Y., Chi, J., Li, W., Liu, C.-N., Xu, Y., Li, Y., Wang, J., Wu, J., Wang, R., et al. (2025) · Applied Biochemistry and Biotechnology · doi:10.1007/s12010-025-05265-6 · Cited by 1 · see citing works
“Isocitrate can be converted into acetyl-CoA, which promotes histone acetylation, leading to an increase in IL-6 and IL-10 production [44, 45].”
Vassileff, N., Spiers, J. G., Juliani, J., Lowe, R. G. T., Datta, K. K., & Hill, A. F. (2024) · Journal of Extracellular Biology · doi:10.1002/jex2.165 · Cited by 3 · see citing works
Correlation between Nod-like Receptor Protein 3 Inflammasome and Diabetic Dry Eye
Zhao, X., & Zhang, R. (2022) · Indian Journal of Pharmaceutical Sciences · doi:10.36468/pharmaceutical-sciences.spl.590 · Cited by 1 · see citing works
Role of Metabolism in Regulating Immune Cell Fate Decisions
Ohradanova-Repic, A., Boes, M., & Stockinger, H. (2020) · Frontiers Research Topics · doi:10.3389/978-2-88963-721-8 · Cited by 1
Photo-downregulation of SIRT4 mitigates aging in mice by enhancing H3K9ac via fatty acid metabolismPreprint
Deng, F., Yang, R., Niu, J., Wang, M., Liu, Y., Li, X., Gao, Z., Yang, L., Liu, H., Yang, Y. Q., et al. (2026) · eLife · doi:10.7554/elife.111498
“On the other hand, inflammatory signals such as TNF-α can activate IKK and phosphorylate p65, leading to local H3K9ac enrichment at SASP inflammatory gene loci, including IL-6 and IL-8 ( Vandenbon et al., 2018 ; Hu et al., 2016 ; Chang and Guarente, 2013 ; Adamkova et al., 2017 ).”
Ryguła, I., Rosiek, V., & Kos‐Kudła, B. (2026) · Cancers · doi:10.3390/cancers18142257
“In addition, IL-6 expression is subject to epigenetic regulation [34–39].”
Metabolic changes and functional activity of macrophages in homeostasis and in inflammation (review)
Yurakova, T. R., Gorshkova, E. A., Nosenko, M. A., & Drutskaya, M. S. (2024) · Biochemistry (Moscow) · doi:10.31857/s0320972524050047
The Role of Changes in Structure and Dynamics of Chromatin due to COVID-19
Bigildeev, A., Alekseev, V. I., Gribkova, A. K., Timokhin, G. S., Komarova, G. A., & Shaytan, A. К. (2024) · Russian Journal of Genetics · doi:10.1134/s1022795424010034
“…and interleukins (IL2, IL7, IL10, GSCF, IP10, MCP1, MIP1A, TNF α , etc.) in the blood plasma of patients with severe COVID-19 [132], and earlier immunological studies reported changes in the ratio of eu-and heterochromatin marks in the promoters of pro-inflammatory genes in immune cells [133, 134].”
- Authors
- Hu, L., Yu, Y., Huang, H., Fan, H., Hu, L., Yin, C., Li, K., Fulton, D. J. R., & Chen, F.
- Affiliations
- Nanjing Medical University (CN)
- Augusta University (US)
- Corresponding author
- Chen, Feng
- Venue
- Frontiers in Immunology
- Publisher
- Frontiers Media SA
- Published
- 2017-01-30
- Volume
- 7
- Pages
- 696-696
- ISSN
- 1664-3224 (ISSN-L)
- PMC
- PMC5276821
- OpenAlex
- W2580243775
- Cited by
- 100
- References
- 69
- Citations by year
- 2026: 4 · 2025: 7 · 2024: 13 · 2023: 12 · 2022: 12 · 2021: 14 · 2020: 16 · 2019: 8 · 2018: 10 · 2017: 4
- FWCI
- 10.65
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- cc-by
- Locations
- Frontiers in Immunology (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Funders
- National Natural Science Foundation of China (81400033, 81570378)
- Topics
- Health Sciences › Medicine › Surgery › Paraquat toxicity studies and treatments
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Interstitial Lung Diseases and Idiopathic Pulmonary Fibrosis
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Epigenetics and DNA Methylation
- Keywords
- interleukin-6, histone acetylation, histone deacetylase inhibition, histone acetyltransferase inhibition, macrophages, epithelial-mesenchymal transition, chromatin accessibility, H3K4me3, H3K9ac, epigenetic regulation
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