Hall of Fame Among Pro-inflammatory Cytokines: Interleukin-6 Gene and Its Transcriptional Regulation Mechanisms

Overview

Journal Front Immunol

Specialty Allergy & Immunology

Date 2017 Jan 10

PMID 28066415

Citations 149

Authors

Yang Luo

Song Guo Zheng

Affiliations

Soon will be listed here.

Abstract

Pro-inflammatory cytokines that are generated by immune system cells and mediate many kinds of immune responses are kinds of endogenous polypeptides. They are also the effectors of the autoimmune system. It is generally accepted that interleukin (IL)-4, IL-6, IL-9, IL-17, and tumor necrosis factor-α are pro-inflammatory cytokines; however, IL-6 becomes a protagonist among them since it predominately induces pro-inflammatory signaling and regulates massive cellular processes. It has been ascertained that IL-6 is associated with a large number of diseases with inflammatory background, such as anemia of chronic diseases, angiogenesis acute-phase response, bone metabolism, cartilage metabolism, and multiple cancers. Despite great progress in the relative field, the targeted regulation of IL-6 response for therapeutic benefits remains incompletely to be understood. Therefore, it is conceivable that understanding mechanisms of IL-6 from the perspective of gene regulation can better facilitate to determine the pathogenesis of the disease, providing more solid scientific basis for clinical treatment translation. In this review, we summarize the candidate genes that have been implicated in clinical target therapy from the perspective of gene transcription regulation.

Citing Articles

Crosstalk Between Antioxidants and Adipogenesis: Mechanistic Pathways and Their Roles in Metabolic Health.

Fu M, Yoon K, Ha J, Kang I, Choe W Antioxidants (Basel). 2025; 14(2).

PMID: 40002389 PMC: 11852089. DOI: 10.3390/antiox14020203.

The Role of Umbilical Cord Mesenchymal Stem Cell-Derived Extracellular Vesicles in Modulating Dermal Fibroblast Activity: A Pathway to Enhanced Tissue Regeneration.

Barathan M, Ham K, Wong H, Law J Biology (Basel). 2025; 14(2).

PMID: 40001918 PMC: 11852171. DOI: 10.3390/biology14020150.

Integrated proteogenomic characterization of ampullary adenocarcinoma.

Zhang Q, Xu X, Jiang D, Wang Y, Wang H, Zhu J Cell Discov. 2025; 11(1):2.

PMID: 39762212 PMC: 11704194. DOI: 10.1038/s41421-024-00742-4.

Mathematical model of the inflammatory response to acute and prolonged lipopolysaccharide exposure in humans.

Relouw F, Kox M, Taal H, Koch B, Prins M, Van Riel N NPJ Syst Biol Appl. 2024; 10(1):146.

PMID: 39638779 PMC: 11621538. DOI: 10.1038/s41540-024-00473-y.

Rapid cyclic stretching induces a synthetic, proinflammatory phenotype in cultured human intestinal smooth muscle, with the potential to alter signaling to adjacent bowel cells.

Wolfson S, Beigel K, Anderson S, Deal B, Weiner M, Lee S bioRxiv. 2024; .

PMID: 39464046 PMC: 11507745. DOI: 10.1101/2024.10.12.617767.

References

Ershler W, Keller E . Age-associated increased interleukin-6 gene expression, late-life diseases, and frailty. Annu Rev Med. 2000; 51:245-70. DOI: 10.1146/annurev.med.51.1.245. View

Terry C, Loukaci V, Green F . Cooperative influence of genetic polymorphisms on interleukin 6 transcriptional regulation. J Biol Chem. 2000; 275(24):18138-44. DOI: 10.1074/jbc.M000379200. View

Zhang Q, Zhao K, Shen Q, Han Y, Gu Y, Li X . Tet2 is required to resolve inflammation by recruiting Hdac2 to specifically repress IL-6. Nature. 2015; 525(7569):389-393. PMC: 4697747. DOI: 10.1038/nature15252. View

Ray A, Tatter S, May L, Sehgal P . Activation of the human "beta 2-interferon/hepatocyte-stimulating factor/interleukin 6" promoter by cytokines, viruses, and second messenger agonists. Proc Natl Acad Sci U S A. 1988; 85(18):6701-5. PMC: 282045. DOI: 10.1073/pnas.85.18.6701. View

Caldenhoven E, Liden J, Wissink S, van de Stolpe A, Raaijmakers J, Koenderman L . Negative cross-talk between RelA and the glucocorticoid receptor: a possible mechanism for the antiinflammatory action of glucocorticoids. Mol Endocrinol. 1995; 9(4):401-12. DOI: 10.1210/mend.9.4.7659084. View

Metz R, Ziff E . cAMP stimulates the C/EBP-related transcription factor rNFIL-6 to trans-locate to the nucleus and induce c-fos transcription. Genes Dev. 1991; 5(10):1754-66. DOI: 10.1101/gad.5.10.1754. View

Akira S, Hirano T, Taga T, Kishimoto T . Biology of multifunctional cytokines: IL 6 and related molecules (IL 1 and TNF). FASEB J. 1990; 4(11):2860-7. View

Neurath M, Finotto S . IL-6 signaling in autoimmunity, chronic inflammation and inflammation-associated cancer. Cytokine Growth Factor Rev. 2011; 22(2):83-9. DOI: 10.1016/j.cytogfr.2011.02.003. View

Fishman D, Faulds G, Jeffery R, Mohamed-Ali V, Yudkin J, Humphries S . The effect of novel polymorphisms in the interleukin-6 (IL-6) gene on IL-6 transcription and plasma IL-6 levels, and an association with systemic-onset juvenile chronic arthritis. J Clin Invest. 1998; 102(7):1369-76. PMC: 508984. DOI: 10.1172/JCI2629. View

10.

Ancrile B, OHayer K, Counter C . Oncogenic ras-induced expression of cytokines: a new target of anti-cancer therapeutics. Mol Interv. 2008; 8(1):22-7. PMC: 2788125. DOI: 10.1124/mi.8.1.6. View

11.

Zhang Y, Lin J, Vilcek J . Synthesis of interleukin 6 (interferon-beta 2/B cell stimulatory factor 2) in human fibroblasts is triggered by an increase in intracellular cyclic AMP. J Biol Chem. 1988; 263(13):6177-82. View

12.

Sehgal P, Zilberstein A, Ruggieri R, May L, A Ferguson-Smith , Slate D . Human chromosome 7 carries the beta 2 interferon gene. Proc Natl Acad Sci U S A. 1986; 83(14):5219-22. PMC: 323922. DOI: 10.1073/pnas.83.14.5219. View

13.

Sen R, Baltimore D . Inducibility of kappa immunoglobulin enhancer-binding protein Nf-kappa B by a posttranslational mechanism. Cell. 1986; 47(6):921-8. DOI: 10.1016/0092-8674(86)90807-x. View

14.

Akira S, Isshiki H, Sugita T, TANABE O, Kinoshita S, Nishio Y . A nuclear factor for IL-6 expression (NF-IL6) is a member of a C/EBP family. EMBO J. 1990; 9(6):1897-906. PMC: 551896. DOI: 10.1002/j.1460-2075.1990.tb08316.x. View

15.

Garbers C, Hermanns H, Schaper F, Muller-Newen G, Grotzinger J, Rose-John S . Plasticity and cross-talk of interleukin 6-type cytokines. Cytokine Growth Factor Rev. 2012; 23(3):85-97. DOI: 10.1016/j.cytogfr.2012.04.001. View

16.

Isshiki H, Akira S, TANABE O, Nakajima T, Shimamoto T, Hirano T . Constitutive and interleukin-1 (IL-1)-inducible factors interact with the IL-1-responsive element in the IL-6 gene. Mol Cell Biol. 1990; 10(6):2757-64. PMC: 360636. DOI: 10.1128/mcb.10.6.2757-2764.1990. View

17.

Gao Y, Tang J, Chen W, Li Q, Nie J, Lin F . Inflammation negatively regulates FOXP3 and regulatory T-cell function via DBC1. Proc Natl Acad Sci U S A. 2015; 112(25):E3246-54. PMC: 4485127. DOI: 10.1073/pnas.1421463112. View

18.

Sehgal P . Regulation of IL6 gene expression. Res Immunol. 1992; 143(7):724-34. DOI: 10.1016/0923-2494(92)80011-9. View

19.

Perkins N, Edwards N, Duckett C, Agranoff A, Schmid R, Nabel G . A cooperative interaction between NF-kappa B and Sp1 is required for HIV-1 enhancer activation. EMBO J. 1993; 12(9):3551-8. PMC: 413631. DOI: 10.1002/j.1460-2075.1993.tb06029.x. View

20.

Tumu V, Govatati S, Guruvaiah P, Deenadayal M, Shivaji S, Bhanoori M . An interleukin-6 gene promoter polymorphism is associated with polycystic ovary syndrome in South Indian women. J Assist Reprod Genet. 2013; 30(12):1541-6. PMC: 3843174. DOI: 10.1007/s10815-013-0111-1. View