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Logo of jcinvestThe Journal of Clinical InvestigationCurrent IssueArchiveSubscriptionAbout the Journal
J Clin Invest. Oct 1, 1998; 102(7): 1369–1376.
PMCID: PMC508984

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.

Abstract

During active disease, patients with systemic-onset juvenile chronic arthritis (S-JCA) demonstrate a rise and fall in serum interleukin-6 (IL-6) that parallels the classic quotidian fever. To investigate the possibility that this cytokine profile results from a difference in the control of IL-6 expression, we examined the 5' flanking region of the IL-6 gene for polymorphisms. A G/C polymorphism was detected at position -174. In a group of 383 healthy men and women from a general practice in North London, the frequency of the C allele was 0.403 (95% confidence interval 0.37-0.44). In comparison, 92 patients with S-JCA had a different overall genotype frequency, especially those with onset of disease at < 5 yr of age. This was mainly due to the statistically significant lower frequency of the CC genotype in this subgroup. When comparing constructs of the 5' flanking region (-550-+61 bp) in a luciferase reporter vector transiently transfected into HeLa cells, the -174C construct showed 0.624+/-0.15-fold lower expression than the -174G construct. After stimulation with LPS or IL-1, expression from the -174C construct did not significantly change after 24 h, whereas expression from the -174G construct increased by 2.35+/-0.10- and 3.60+/-0.26-fold, respectively, compared with the unstimulated level. Plasma levels of IL-6 were also measured in 102 of the healthy subjects, and the C allele was found to be associated with significantly lower levels of plasma IL-6. These results suggest that there is a genetically determined difference in the degree of the IL-6 response to stressful stimuli between individuals. The reduced frequency of the potentially protective CC genotype in young S-JCA patients may contribute to its pathogenesis. Similarly the individual's IL-6 genotype may be highly relevant in other conditions where IL-6 has been implicated, such as atherosclerosis.

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Selected References

These references are in PubMed. This may not be the complete list of references from this article.
  • Wallace CA, Levinson JE. Juvenile rheumatoid arthritis: outcome and treatment for the 1990s. Rheum Dis Clin North Am. 1991 Nov;17(4):891–905. [PubMed]
  • Fishman D, Rooney M, Woo P. Successful management of reactive haemophagocytic syndrome in systemic-onset juvenile chronic arthritis. Br J Rheumatol. 1995 Sep;34(9):888–888. [PubMed]
  • de Benedetti F, Massa M, Robbioni P, Ravelli A, Burgio GR, Martini A. Correlation of serum interleukin-6 levels with joint involvement and thrombocytosis in systemic juvenile rheumatoid arthritis. Arthritis Rheum. 1991 Sep;34(9):1158–1163. [PubMed]
  • Lepore L, Pennesi M, Saletta S, Perticarari S, Presani G, Prodan M. Study of IL-2, IL-6, TNF alpha, IFN gamma and beta in the serum and synovial fluid of patients with juvenile chronic arthritis. Clin Exp Rheumatol. 1994 Sep-Oct;12(5):561–565. [PubMed]
  • Mangge H, Kenzian H, Gallistl S, Neuwirth G, Liebmann P, Kaulfersch W, Beaufort F, Muntean W, Schauenstein K. Serum cytokines in juvenile rheumatoid arthritis. Correlation with conventional inflammation parameters and clinical subtypes. Arthritis Rheum. 1995 Feb;38(2):211–220. [PubMed]
  • De Benedetti F, Pignatti P, Massa M, Sartirana P, Ravelli A, Martini A. Circulating levels of interleukin 1 beta and of interleukin 1 receptor antagonist in systemic juvenile chronic arthritis. Clin Exp Rheumatol. 1995 Nov-Dec;13(6):779–784. [PubMed]
  • Rooney M, David J, Symons J, Di Giovine F, Varsani H, Woo P. Inflammatory cytokine responses in juvenile chronic arthritis. Br J Rheumatol. 1995 May;34(5):454–460. [PubMed]
  • Prieur AM, Roux-Lombard P, Dayer JM. Dynamics of fever and the cytokine network in systemic juvenile arthritis. Rev Rhum Engl Ed. 1996 Mar;63(3):163–170. [PubMed]
  • Tilg H, Trehu E, Atkins MB, Dinarello CA, Mier JW. Interleukin-6 (IL-6) as an anti-inflammatory cytokine: induction of circulating IL-1 receptor antagonist and soluble tumor necrosis factor receptor p55. Blood. 1994 Jan 1;83(1):113–118. [PubMed]
  • Jordan M, Otterness IG, Ng R, Gessner A, Röllinghoff M, Beuscher HU. Neutralization of endogenous IL-6 suppresses induction of IL-1 receptor antagonist. J Immunol. 1995 Apr 15;154(8):4081–4090. [PubMed]
  • Yoshizaki K, Matsuda T, Nishimoto N, Kuritani T, Taeho L, Aozasa K, Nakahata T, Kawai H, Tagoh H, Komori T, et al. Pathogenic significance of interleukin-6 (IL-6/BSF-2) in Castleman's disease. Blood. 1989 Sep;74(4):1360–1367. [PubMed]
  • Dao DD, Sawyer JR, Epstein J, Hoover RG, Barlogie B, Tricot G. Deletion of the retinoblastoma gene in multiple myeloma. Leukemia. 1994 Aug;8(8):1280–1284. [PubMed]
  • Helle M, Brakenhoff JP, De Groot ER, Aarden LA. Interleukin 6 is involved in interleukin 1-induced activities. Eur J Immunol. 1988 Jun;18(6):957–959. [PubMed]
  • Mulé JJ, Marcus SG, Yang JC, Weber JS, Rosenberg SA. Clinical application of IL6 in cancer therapy. Res Immunol. 1992 Sep;143(7):777–779. [PubMed]
  • Elliott MJ, Maini RN, Feldmann M, Long-Fox A, Charles P, Katsikis P, Brennan FM, Walker J, Bijl H, Ghrayeb J, et al. Treatment of rheumatoid arthritis with chimeric monoclonal antibodies to tumor necrosis factor alpha. Arthritis Rheum. 1993 Dec;36(12):1681–1690. [PubMed]
  • Elliott MJ, Woo P, Charles P, Long-Fox A, Woody JN, Maini RN. Suppression of fever and the acute-phase response in a patient with juvenile chronic arthritis treated with monoclonal antibody to tumour necrosis factor-alpha (cA2). Br J Rheumatol. 1997 May;36(5):589–593. [PubMed]
  • Wilson AG, Symons JA, McDowell TL, McDevitt HO, Duff GW. Effects of a polymorphism in the human tumor necrosis factor alpha promoter on transcriptional activation. Proc Natl Acad Sci U S A. 1997 Apr 1;94(7):3195–3199. [PMC free article] [PubMed]
  • Angotti E, Mele E, Costanzo F, Avvedimento EV. A polymorphism (G-->A transition) in the -78 position of the apolipoprotein A-I promoter increases transcription efficiency. J Biol Chem. 1994 Jul 1;269(26):17371–17374. [PubMed]
  • Danis VA, Millington M, Hyland VJ, Grennan D. Cytokine production by normal human monocytes: inter-subject variation and relationship to an IL-1 receptor antagonist (IL-1Ra) gene polymorphism. Clin Exp Immunol. 1995 Feb;99(2):303–310. [PMC free article] [PubMed]
  • McDowell TL, Symons JA, Ploski R, Førre O, Duff GW. A genetic association between juvenile rheumatoid arthritis and a novel interleukin-1 alpha polymorphism. Arthritis Rheum. 1995 Feb;38(2):221–228. [PubMed]
  • McGuire W, Hill AV, Allsopp CE, Greenwood BM, Kwiatkowski D. Variation in the TNF-alpha promoter region associated with susceptibility to cerebral malaria. Nature. 1994 Oct 6;371(6497):508–510. [PubMed]
  • Cabrera M, Shaw MA, Sharples C, Williams H, Castes M, Convit J, Blackwell JM. Polymorphism in tumor necrosis factor genes associated with mucocutaneous leishmaniasis. J Exp Med. 1995 Nov 1;182(5):1259–1264. [PMC free article] [PubMed]
  • Roy S, McGuire W, Mascie-Taylor CG, Saha B, Hazra SK, Hill AV, Kwiatkowski D. Tumor necrosis factor promoter polymorphism and susceptibility to lepromatous leprosy. J Infect Dis. 1997 Aug;176(2):530–532. [PubMed]
  • Kunkel LM, Smith KD, Boyer SH, Borgaonkar DS, Wachtel SS, Miller OJ, Breg WR, Jones HW, Jr, Rary JM. Analysis of human Y-chromosome-specific reiterated DNA in chromosome variants. Proc Natl Acad Sci U S A. 1977 Mar;74(3):1245–1249. [PMC free article] [PubMed]
  • Gould MM, Mohamed-Ali V, Goubet SA, Yudkin JS, Haines AP. Microalbuminuria: associations with height and sex in non-diabetic subjects. BMJ. 1993 Jan 23;306(6872):240–242. [PMC free article] [PubMed]
  • Yudkin JS, Andres C, Mohamed-Ali V, Gould M, Panahloo A, Haines AP, Humphries S, Talmud P. The angiotensin-converting enzyme gene and the angiotensin II type I receptor gene as candidate genes for microalbuminuria. A study in nondiabetic and non-insulin-dependent diabetic subjects. Arterioscler Thromb Vasc Biol. 1997 Oct;17(10):2188–2191. [PubMed]
  • Cruickshank JK, Cooper J, Burnett M, MacDuff J, Drubra U. Ethnic differences in fasting plasma C-peptide and insulin in relation to glucose tolerance and blood pressure. Lancet. 1991 Oct 5;338(8771):842–847. [PubMed]
  • Miller SA, Dykes DD, Polesky HF. A simple salting out procedure for extracting DNA from human nucleated cells. Nucleic Acids Res. 1988 Feb 11;16(3):1215–1215. [PMC free article] [PubMed]
  • Orita M, Suzuki Y, Sekiya T, Hayashi K. Rapid and sensitive detection of point mutations and DNA polymorphisms using the polymerase chain reaction. Genomics. 1989 Nov;5(4):874–879. [PubMed]
  • Gudnason V, Mak YT, Betteridge J, McCarthy SN, Humphries S. Use of the single-strand conformational polymorphism method to detect recurrent and novel mutations in the low-density lipoprotein receptor gene in patients with familial hypercholesterolaemia: detection of a novel mutation Asp200-->Gly. Clin Investig. 1993 Apr;71(4):331–337. [PubMed]
  • Day IN, Humphries SE. Electrophoresis for genotyping: microtiter array diagonal gel electrophoresis on horizontal polyacrylamide gels, hydrolink, or agarose. Anal Biochem. 1994 Nov 1;222(2):389–395. [PubMed]
  • Graham FL, van der Eb AJ. A new technique for the assay of infectivity of human adenovirus 5 DNA. Virology. 1973 Apr;52(2):456–467. [PubMed]
  • Mohamed-Ali V, Goodrick S, Rawesh A, Katz DR, Miles JM, Yudkin JS, Klein S, Coppack SW. Subcutaneous adipose tissue releases interleukin-6, but not tumor necrosis factor-alpha, in vivo. J Clin Endocrinol Metab. 1997 Dec;82(12):4196–4200. [PubMed]
  • Yasukawa K, Hirano T, Watanabe Y, Muratani K, Matsuda T, Nakai S, Kishimoto T. Structure and expression of human B cell stimulatory factor-2 (BSF-2/IL-6) gene. EMBO J. 1987 Oct;6(10):2939–2945. [PMC free article] [PubMed]
  • Hollon T, Yoshimura FK. Variation in enzymatic transient gene expression assays. Anal Biochem. 1989 Nov 1;182(2):411–418. [PubMed]
  • Bowcock AM, Kidd JR, Lathrop GM, Daneshvar L, May LT, Ray A, Sehgal PB, Kidd KK, Cavalli-Sforza LL. The human "interferon-beta 2/hepatocyte stimulating factor/interleukin-6" gene: DNA polymorphism studies and localization to chromosome 7p21. Genomics. 1988 Jul;3(1):8–16. [PubMed]
  • Bowcock AM, Ray A, Erlich H, Sehgal PB. Rapid detection and sequencing of alleles in the 3' flanking region of the interleukin-6 gene. Nucleic Acids Res. 1989 Sep 12;17(17):6855–6864. [PMC free article] [PubMed]
  • Fugger L, Morling N, Bendtzen K, Ryder L, Andersen V, Heilman C, Karup Pedersen F, Friis J, Halbert P, Svejgaard A. IL-6 gene polymorphism in rheumatoid arthritis, pauciarticular juvenile rheumatoid arthritis, systemic lupus erythematosus, and in healthy Danes. J Immunogenet. 1989 Dec;16(6):461–465. [PubMed]
  • Linker-Israeli M, Wallace DJ, Prehn JL, Nand R, Li L, Klinenberg JR. A greater variability in the 3' flanking region of the IL-6 gene in patients with systemic lupus erythematosus (SLE). Autoimmunity. 1996;23(3):199–209. [PubMed]
  • Murray RE, McGuigan F, Grant SF, Reid DM, Ralston SH. Polymorphisms of the interleukin-6 gene are associated with bone mineral density. Bone. 1997 Jul;21(1):89–92. [PubMed]
  • Ray A, LaForge KS, Sehgal PB. On the mechanism for efficient repression of the interleukin-6 promoter by glucocorticoids: enhancer, TATA box, and RNA start site (Inr motif) occlusion. Mol Cell Biol. 1990 Nov;10(11):5736–5746. [PMC free article] [PubMed]
  • Liu Y, Bernard HU, Apt D. NFI-B3, a novel transcriptional repressor of the nuclear factor I family, is generated by alternative RNA processing. J Biol Chem. 1997 Apr 18;272(16):10739–10745. [PubMed]
  • Rein T, Förster R, Krause A, Winnacker EL, Zorbas H. Organization of the alpha-globin promoter and possible role of nuclear factor I in an alpha-globin-inducible and a noninducible cell line. J Biol Chem. 1995 Aug 18;270(33):19643–19650. [PubMed]

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