PMCCPMCCPMCC

Search tips
Search criteria 

Advanced

 
Logo of jcinvestThe Journal of Clinical Investigation
 
J Clin Invest. 1996 January 15; 97(2): 421–430.
PMCID: PMC507033

Rhinovirus stimulation of interleukin-6 in vivo and in vitro. Evidence for nuclear factor kappa B-dependent transcriptional activation.

Abstract

To further understand the biology of rhinovirus (RV), we determined whether IL-6 was produced during RV infections and characterized the mechanism by which RV stimulates lung cell IL-6 production. In contrast to normals and minimally symptomatic volunteers, IL-6 was detected in the nasal washings from patients who developed colds after RV challenge. RV14 and RV1A, major and minor receptor group RVs, respectively, were potent stimulators of IL-6 protein production in vitro. These effects were associated with significant increases in IL-6 mRNA accumulation and gene transcription. RV was also a potent stimulator of IL-6 promoter-driven luciferase activity. This stimulation was modestly decreased by mutation of the nuclear factor (NF)-IL-6 site and abrogated by mutation of the NF-kappa B site in this promoter. An NF-kappa B-DNA binding activity, mediated by p65, p50, and p52 NF-kappa B moieties, was rapidly induced in RV-infected cells. Activator protein 1-DNA binding was not similarly altered. These studies demonstrate that IL-6 is produced during symptomatic RV infections, that RVs are potent stimulators of IL-6 elaboration, and that RV stimulation IL-6 production is mediated by an NF-kappa B-dependent transcriptional stimulation pathway. IL-6 may play an important role in the pathogenesis of RV infection, and NF-kappa B activation is likely to be an important event in RV-induced pathologies.

Full Text

The Full Text of this article is available as a PDF (315K).

Selected References

These references are in PubMed. This may not be the complete list of references from this article.
  • Evans FO, Jr, Sydnor JB, Moore WE, Moore GR, Manwaring JL, Brill AH, Jackson RT, Hanna S, Skaar JS, Holdeman LV, et al. Sinusitis of the maxillary antrum. N Engl J Med. 1975 Oct 9;293(15):735–739. [PubMed]
  • Cate TR, Douglas RG, Jr, Couch RB. Interferon and resistance to upper respiratory virus illness. Proc Soc Exp Biol Med. 1969 Jun;131(2):631–636. [PubMed]
  • Cate TR, Rossen RD, Douglas RG, Jr, Butler WT, Couch RB. The role of nasal secretion and serum antibody in the rhinovirus common cold. Am J Epidemiol. 1966 Sep;84(2):352–363. [PubMed]
  • Douglas RG, Jr, Alford BR, Couch RB. Atraumatic nasal biopsy for studies of respiratory virus infection in volunteers. Antimicrob Agents Chemother (Bethesda) 1968;8:340–343. [PubMed]
  • Hamory BH, Hendley JO, Gwaltney JM., Jr Rhinovirus growth in nasal polyp organ culture. Proc Soc Exp Biol Med. 1977 Sep;155(4):577–582. [PubMed]
  • Winther B, Farr B, Turner RB, Hendley JO, Gwaltney JM, Jr, Mygind N. Histopathologic examination and enumeration of polymorphonuclear leukocytes in the nasal mucosa during experimental rhinovirus colds. Acta Otolaryngol Suppl. 1984;413:19–24. [PubMed]
  • Proud D, Reynolds CJ, Lacapra S, Kagey-Sobotka A, Lichtenstein LM, Naclerio RM. Nasal provocation with bradykinin induces symptoms of rhinitis and a sore throat. Am Rev Respir Dis. 1988 Mar;137(3):613–616. [PubMed]
  • Proud D, Gwaltney JM, Jr, Hendley JO, Dinarello CA, Gillis S, Schleimer RP. Increased levels of interleukin-1 are detected in nasal secretions of volunteers during experimental rhinovirus colds. J Infect Dis. 1994 May;169(5):1007–1013. [PubMed]
  • Akira S, Taga T, Kishimoto T. Interleukin-6 in biology and medicine. Adv Immunol. 1993;54:1–78. [PubMed]
  • Noah TL, Becker S. Respiratory syncytial virus-induced cytokine production by a human bronchial epithelial cell line. Am J Physiol. 1993 Nov;265(5 Pt 1):L472–L478. [PubMed]
  • DiCosmo BF, Geba GP, Picarella D, Elias JA, Rankin JA, Stripp BR, Whitsett JA, Flavell RA. Airway epithelial cell expression of interleukin-6 in transgenic mice. Uncoupling of airway inflammation and bronchial hyperreactivity. J Clin Invest. 1994 Nov;94(5):2028–2035. [PMC free article] [PubMed]
  • Ramsay AJ, Husband AJ, Ramshaw IA, Bao S, Matthaei KI, Koehler G, Kopf M. The role of interleukin-6 in mucosal IgA antibody responses in vivo. Science. 1994 Apr 22;264(5158):561–563. [PubMed]
  • Ramsay AJ, Leong KH, Boyle D, Ruby J, Ramshaw IA. Enhancement of mucosal IgA responses by interleukins 5 and 6 encoded in recombinant vaccine vectors. Reprod Fertil Dev. 1994;6(3):389–392. [PubMed]
  • Fujihashi K, Kono Y, Kiyono H. Effects of IL6 on B cells in mucosal immune response and inflammation. Res Immunol. 1992 Sep;143(7):744–749. [PubMed]
  • Farr BM, Gwaltney JM, Jr, Hendley JO, Hayden FG, Naclerio RM, McBride T, Doyle WJ, Sorrentino JV, Riker DK, Proud D. A randomized controlled trial of glucocorticoid prophylaxis against experimental rhinovirus infection. J Infect Dis. 1990 Nov;162(5):1173–1177. [PubMed]
  • JACKSON GG, DOWLING HF, SPIESMAN IG, BOAND AV. Transmission of the common cold to volunteers under controlled conditions. I. The common cold as a clinical entity. AMA Arch Intern Med. 1958 Feb;101(2):267–278. [PubMed]
  • Elias JA, Tang W, Horowitz MC. Cytokine and hormonal stimulation of human osteosarcoma interleukin-11 production. Endocrinology. 1995 Feb;136(2):489–498. [PubMed]
  • Lu ZY, Zhang XG, Gu ZJ, Yasukawa K, Amiot M, Etrillard M, Bataille R, Klein B. A highly sensitive quantitative bioassay for human interleukin-11. J Immunol Methods. 1994 Jul 12;173(1):19–26. [PubMed]
  • Chomczynski P, Sacchi N. Single-step method of RNA isolation by acid guanidinium thiocyanate-phenol-chloroform extraction. Anal Biochem. 1987 Apr;162(1):156–159. [PubMed]
  • Feinberg AP, Vogelstein B. A technique for radiolabeling DNA restriction endonuclease fragments to high specific activity. Anal Biochem. 1983 Jul 1;132(1):6–13. [PubMed]
  • Elias JA, Lentz V. IL-1 and tumor necrosis factor synergistically stimulate fibroblast IL-6 production and stabilize IL-6 messenger RNA. J Immunol. 1990 Jul 1;145(1):161–166. [PubMed]
  • Elias JA, Zheng T, Whiting NL, Trow TK, Merrill WW, Zitnik R, Ray P, Alderman EM. IL-1 and transforming growth factor-beta regulation of fibroblast-derived IL-11. J Immunol. 1994 Mar 1;152(5):2421–2429. [PubMed]
  • Ray A, Tatter SB, May LT, Sehgal PB. 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 Sep;85(18):6701–6705. [PubMed]
  • Ray A, Prefontaine KE. Physical association and functional antagonism between the p65 subunit of transcription factor NF-kappa B and the glucocorticoid receptor. Proc Natl Acad Sci U S A. 1994 Jan 18;91(2):752–756. [PubMed]
  • Fashena SJ, Tang WL, Sarr T, Ruddle NH. The murine lymphotoxin gene promoter. Characterization and negative regulation. J Immunol. 1990 Jul 1;145(1):177–183. [PubMed]
  • Eustice DC, Feldman PA, Colberg-Poley AM, Buckery RM, Neubauer RH. A sensitive method for the detection of beta-galactosidase in transfected mammalian cells. Biotechniques. 1991 Dec;11(6):739–743. [PubMed]
  • Schreiber E, Matthias P, Müller MM, Schaffner W. Rapid detection of octamer binding proteins with 'mini-extracts', prepared from a small number of cells. Nucleic Acids Res. 1989 Aug 11;17(15):6419–6419. [PMC free article] [PubMed]
  • Bradford MM. A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein-dye binding. Anal Biochem. 1976 May 7;72:248–254. [PubMed]
  • Tomassini JE, Graham D, DeWitt CM, Lineberger DW, Rodkey JA, Colonno RJ. cDNA cloning reveals that the major group rhinovirus receptor on HeLa cells is intercellular adhesion molecule 1. Proc Natl Acad Sci U S A. 1989 Jul;86(13):4907–4911. [PubMed]
  • Hofer F, Gruenberger M, Kowalski H, Machat H, Huettinger M, Kuechler E, Blaas D. Members of the low density lipoprotein receptor family mediate cell entry of a minor-group common cold virus. Proc Natl Acad Sci U S A. 1994 Mar 1;91(5):1839–1842. [PubMed]
  • Hoorn B, Tyrrell DA. Organ cultures in virology. Prog Med Virol. 1969;11:408–450. [PubMed]
  • Turner RB, Hendley JO, Gwaltney JM., Jr Shedding of infected ciliated epithelial cells in rhinovirus colds. J Infect Dis. 1982 Jun;145(6):849–853. [PubMed]
  • Turner RB. The role of neutrophils in the pathogenesis of rhinovirus infections. Pediatr Infect Dis J. 1990 Nov;9(11):832–835. [PubMed]
  • Weissenbach J, Chernajovsky Y, Zeevi M, Shulman L, Soreq H, Nir U, Wallach D, Perricaudet M, Tiollais P, Revel M. Two interferon mRNAs in human fibroblasts: in vitro translation and Escherichia coli cloning studies. Proc Natl Acad Sci U S A. 1980 Dec;77(12):7152–7156. [PubMed]
  • Noah TL, Henderson FW, Wortman IA, Devlin RB, Handy J, Koren HS, Becker S. Nasal cytokine production in viral acute upper respiratory infection of childhood. J Infect Dis. 1995 Mar;171(3):584–592. [PubMed]
  • LeMay LG, Vander AJ, Kluger MJ. Role of interleukin 6 in fever in rats. Am J Physiol. 1990 Mar;258(3 Pt 2):R798–R803. [PubMed]
  • Baumann H, Gauldie J. Regulation of hepatic acute phase plasma protein genes by hepatocyte stimulating factors and other mediators of inflammation. Mol Biol Med. 1990 Apr;7(2):147–159. [PubMed]
  • Uyttenhove C, Coulie PG, Van Snick J. T cell growth and differentiation induced by interleukin-HP1/IL-6, the murine hybridoma/plasmacytoma growth factor. J Exp Med. 1988 Apr 1;167(4):1417–1427. [PMC free article] [PubMed]
  • Muraguchi A, Hirano T, Tang B, Matsuda T, Horii Y, Nakajima K, Kishimoto T. The essential role of B cell stimulatory factor 2 (BSF-2/IL-6) for the terminal differentiation of B cells. J Exp Med. 1988 Feb 1;167(2):332–344. [PMC free article] [PubMed]
  • Fraenkel DJ, Bardin PG, Sanderson G, Lampe F, Johnston SL, Holgate ST. Lower airways inflammation during rhinovirus colds in normal and in asthmatic subjects. Am J Respir Crit Care Med. 1995 Mar;151(3 Pt 1):879–886. [PubMed]
  • Siebenlist U, Franzoso G, Brown K. Structure, regulation and function of NF-kappa B. Annu Rev Cell Biol. 1994;10:405–455. [PubMed]
  • Matsusaka T, Fujikawa K, Nishio Y, Mukaida N, Matsushima K, Kishimoto T, Akira S. Transcription factors NF-IL6 and NF-kappa B synergistically activate transcription of the inflammatory cytokines, interleukin 6 and interleukin 8. Proc Natl Acad Sci U S A. 1993 Nov 1;90(21):10193–10197. [PubMed]
  • Sambucetti LC, Cherrington JM, Wilkinson GW, Mocarski ES. NF-kappa B activation of the cytomegalovirus enhancer is mediated by a viral transactivator and by T cell stimulation. EMBO J. 1989 Dec 20;8(13):4251–4258. [PubMed]
  • Kowalik TF, Wing B, Haskill JS, Azizkhan JC, Baldwin AS, Jr, Huang ES. Multiple mechanisms are implicated in the regulation of NF-kappa B activity during human cytomegalovirus infection. Proc Natl Acad Sci U S A. 1993 Feb 1;90(3):1107–1111. [PubMed]
  • Nabel G, Baltimore D. An inducible transcription factor activates expression of human immunodeficiency virus in T cells. Nature. 1987 Apr 16;326(6114):711–713. [PubMed]
  • Pierce JW, Lenardo M, Baltimore D. Oligonucleotide that binds nuclear factor NF-kappa B acts as a lymphoid-specific and inducible enhancer element. Proc Natl Acad Sci U S A. 1988 Mar;85(5):1482–1486. [PubMed]
  • Dunn SM, Coles LS, Lang RK, Gerondakis S, Vadas MA, Shannon MF. Requirement for nuclear factor (NF)-kappa B p65 and NF-interleukin-6 binding elements in the tumor necrosis factor response region of the granulocyte colony-stimulating factor promoter. Blood. 1994 May 1;83(9):2469–2479. [PubMed]
  • Stein B, Cogswell PC, Baldwin AS., Jr Functional and physical associations between NF-kappa B and C/EBP family members: a Rel domain-bZIP interaction. Mol Cell Biol. 1993 Jul;13(7):3964–3974. [PMC free article] [PubMed]
  • Mori N, Shirakawa F, Shimizu H, Murakami S, Oda S, Yamamoto K, Eto S. Transcriptional regulation of the human interleukin-6 gene promoter in human T-cell leukemia virus type I-infected T-cell lines: evidence for the involvement of NF-kappa B. Blood. 1994 Nov 1;84(9):2904–2911. [PubMed]
  • Mahé Y, Mukaida N, Kuno K, Akiyama M, Ikeda N, Matsushima K, Murakami S. Hepatitis B virus X protein transactivates human interleukin-8 gene through acting on nuclear factor kB and CCAAT/enhancer-binding protein-like cis-elements. J Biol Chem. 1991 Jul 25;266(21):13759–13763. [PubMed]
  • Gwaltney JM, Jr, Hendley JO, Simon G, Jordan WS., Jr Rhinovirus infections in an industrial population. I. The occurrence of illness. N Engl J Med. 1966 Dec 8;275(23):1261–1268. [PubMed]
  • Monto AS, Ullman BM. Acute respiratory illness in an American community. The Tecumseh study. JAMA. 1974 Jan 14;227(2):164–169. [PubMed]
  • Palombella VJ, Rando OJ, Goldberg AL, Maniatis T. The ubiquitin-proteasome pathway is required for processing the NF-kappa B1 precursor protein and the activation of NF-kappa B. Cell. 1994 Sep 9;78(5):773–785. [PubMed]
  • Staal FJ, Roederer M, Herzenberg LA, Herzenberg LA. Intracellular thiols regulate activation of nuclear factor kappa B and transcription of human immunodeficiency virus. Proc Natl Acad Sci U S A. 1990 Dec;87(24):9943–9947. [PubMed]
  • Kopp E, Ghosh S. Inhibition of NF-kappa B by sodium salicylate and aspirin. Science. 1994 Aug 12;265(5174):956–959. [PubMed]
  • Franzoso G, Biswas P, Poli G, Carlson LM, Brown KD, Tomita-Yamaguchi M, Fauci AS, Siebenlist UK. A family of serine proteases expressed exclusively in myelo-monocytic cells specifically processes the nuclear factor-kappa B subunit p65 in vitro and may impair human immunodeficiency virus replication in these cells. J Exp Med. 1994 Oct 1;180(4):1445–1456. [PMC free article] [PubMed]
  • Schreck R, Grassmann R, Fleckenstein B, Baeuerle PA. Antioxidants selectively suppress activation of NF-kappa B by human T-cell leukemia virus type I Tax protein. J Virol. 1992 Nov;66(11):6288–6293. [PMC free article] [PubMed]
  • Maran A, Maitra RK, Kumar A, Dong B, Xiao W, Li G, Williams BR, Torrence PF, Silverman RH. Blockage of NF-kappa B signaling by selective ablation of an mRNA target by 2-5A antisense chimeras. Science. 1994 Aug 5;265(5173):789–792. [PubMed]

Articles from The Journal of Clinical Investigation are provided here courtesy of American Society for Clinical Investigation