Skip to main content
PMC home page
The Journal of Clinical Investigation logoLink to The Journal of Clinical Investigation
. 1998 Feb 1;101(3):643–649. doi: 10.1172/JCI1355

Local and systemic cytokine responses during experimental human influenza A virus infection. Relation to symptom formation and host defense.

F G Hayden 1, R Fritz 1, M C Lobo 1, W Alvord 1, W Strober 1, S E Straus 1
PMCID: PMC508608  PMID: 9449698

Abstract

To further understand the role of cytokine responses in symptom formation and host defenses in influenza infection, we determined the levels of IL-1beta, IL-2, IL-6, IL-8, IFN-alpha, TGF-beta, and TNF-alpha in nasal lavage fluid, plasma, and serum obtained serially from 19 volunteers experimentally infected with influenza A/Texas/36/91 (H1N1) and correlated these levels with various measures of infection and illness severity. We found that IL-6 and IFN-alpha levels in nasal lavage fluids peaked early (day 2) and correlated directly with viral titers, temperature, mucus production, and symptom scores. IL-6 elevations were also found in the circulation at this time point. In contrast, TNF-alpha responses peaked later (day 3 in plasma, day 4 in nasal fluids), when viral shedding and symptoms were subsiding. Similarly, IL-8 peaked late in the illness course (days 4-6) and correlated only with lower respiratory symptoms, which also occurred late. None of IL-1beta, IL-2, or TGF-beta levels increased significantly. These data implicate IL-6 and IFN-alpha as key factors both in symptom formation and host defense in influenza.

Full Text

The Full Text of this article is available as a PDF (186.6 KB).

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Choi A. M., Jacoby D. B. Influenza virus A infection induces interleukin-8 gene expression in human airway epithelial cells. FEBS Lett. 1992 Sep 14;309(3):327–329. doi: 10.1016/0014-5793(92)80799-m. [DOI] [PubMed] [Google Scholar]
  2. Conn C. A., McClellan J. L., Maassab H. F., Smitka C. W., Majde J. A., Kluger M. J. Cytokines and the acute phase response to influenza virus in mice. Am J Physiol. 1995 Jan;268(1 Pt 2):R78–R84. doi: 10.1152/ajpregu.1995.268.1.R78. [DOI] [PubMed] [Google Scholar]
  3. Cousens L. P., Orange J. S., Su H. C., Biron C. A. Interferon-alpha/beta inhibition of interleukin 12 and interferon-gamma production in vitro and endogenously during viral infection. Proc Natl Acad Sci U S A. 1997 Jan 21;94(2):634–639. doi: 10.1073/pnas.94.2.634. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Gong J. H., Sprenger H., Hinder F., Bender A., Schmidt A., Horch S., Nain M., Gemsa D. Influenza A virus infection of macrophages. Enhanced tumor necrosis factor-alpha (TNF-alpha) gene expression and lipopolysaccharide-triggered TNF-alpha release. J Immunol. 1991 Nov 15;147(10):3507–3513. [PubMed] [Google Scholar]
  5. Green J. A., Charette R. P., Yeh T. J., Smith C. B. Presence of interferon in acute- and convalescent-phase sera of humans with influenza or influenza-like illness of undetermined etiology. J Infect Dis. 1982 Jun;145(6):837–841. doi: 10.1093/infdis/145.6.837. [DOI] [PubMed] [Google Scholar]
  6. Hennet T., Ziltener H. J., Frei K., Peterhans E. A kinetic study of immune mediators in the lungs of mice infected with influenza A virus. J Immunol. 1992 Aug 1;149(3):932–939. [PubMed] [Google Scholar]
  7. Hoofnagle J. H., di Bisceglie A. M. The treatment of chronic viral hepatitis. N Engl J Med. 1997 Jan 30;336(5):347–356. doi: 10.1056/NEJM199701303360507. [DOI] [PubMed] [Google Scholar]
  8. Houde M., Arora D. J. Stimulation of tumor necrosis factor secretion by purified influenza virus neuraminidase. Cell Immunol. 1990 Aug;129(1):104–111. doi: 10.1016/0008-8749(90)90190-3. [DOI] [PubMed] [Google Scholar]
  9. Kaulbach H. C., White M. V., Igarashi Y., Hahn B. K., Kaliner M. A. Estimation of nasal epithelial lining fluid using urea as a marker. J Allergy Clin Immunol. 1993 Sep;92(3):457–465. doi: 10.1016/0091-6749(93)90125-y. [DOI] [PubMed] [Google Scholar]
  10. Lehmann C., Sprenger H., Nain M., Bacher M., Gemsa D. Infection of macrophages by influenza A virus: characteristics of tumour necrosis factor-alpha (TNF alpha) gene expression. Res Virol. 1996 Mar-Jun;147(2-3):123–130. doi: 10.1016/0923-2516(96)80226-3. [DOI] [PubMed] [Google Scholar]
  11. Matsukura S., Kokubu F., Noda H., Tokunaga H., Adachi M. Expression of IL-6, IL-8, and RANTES on human bronchial epithelial cells, NCI-H292, induced by influenza virus A. J Allergy Clin Immunol. 1996 Dec;98(6 Pt 1):1080–1087. doi: 10.1016/s0091-6749(96)80195-3. [DOI] [PubMed] [Google Scholar]
  12. Noah T. L., Henderson F. W., Wortman I. A., Devlin R. B., Handy J., Koren H. S., Becker S. Nasal cytokine production in viral acute upper respiratory infection of childhood. J Infect Dis. 1995 Mar;171(3):584–592. doi: 10.1093/infdis/171.3.584. [DOI] [PubMed] [Google Scholar]
  13. Orange J. S., Biron C. A. An absolute and restricted requirement for IL-12 in natural killer cell IFN-gamma production and antiviral defense. Studies of natural killer and T cell responses in contrasting viral infections. J Immunol. 1996 Feb 1;156(3):1138–1142. [PubMed] [Google Scholar]
  14. Peper R. L., Van Campen H. Tumor necrosis factor as a mediator of inflammation in influenza A viral pneumonia. Microb Pathog. 1995 Sep;19(3):175–183. doi: 10.1006/mpat.1995.0056. [DOI] [PubMed] [Google Scholar]
  15. Peschke T., Bender A., Nain M., Gemsa D. Role of macrophage cytokines in influenza A virus infections. Immunobiology. 1993 Nov;189(3-4):340–355. doi: 10.1016/s0171-2985(11)80365-7. [DOI] [PubMed] [Google Scholar]
  16. Renegar K. B. Influenza virus infections and immunity: a review of human and animal models. Lab Anim Sci. 1992 Jun;42(3):222–232. [PubMed] [Google Scholar]
  17. Rincón M., Anguita J., Nakamura T., Fikrig E., Flavell R. A. Interleukin (IL)-6 directs the differentiation of IL-4-producing CD4+ T cells. J Exp Med. 1997 Feb 3;185(3):461–469. doi: 10.1084/jem.185.3.461. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Ruzek M. C., Miller A. H., Opal S. M., Pearce B. D., Biron C. A. Characterization of early cytokine responses and an interleukin (IL)-6-dependent pathway of endogenous glucocorticoid induction during murine cytomegalovirus infection. J Exp Med. 1997 Apr 7;185(7):1185–1192. doi: 10.1084/jem.185.7.1185. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Sarawar S. R., Carding S. R., Allan W., McMickle A., Fujihashi K., Kiyono H., McGhee J. R., Doherty P. C. Cytokine profiles of bronchoalveolar lavage cells from mice with influenza pneumonia: consequences of CD4+ and CD8+ T cell depletion. Reg Immunol. 1993 May-Aug;5(3-4):142–150. [PubMed] [Google Scholar]
  20. Vacheron F., Rudent A., Perin S., Labarre C., Quero A. M., Guenounou M. Production of interleukin 1 and tumour necrosis factor activities in bronchoalveolar washings following infection of mice by influenza virus. J Gen Virol. 1990 Feb;71(Pt 2):477–479. doi: 10.1099/0022-1317-71-2-477. [DOI] [PubMed] [Google Scholar]
  21. Van Snick J. Interleukin-6: an overview. Annu Rev Immunol. 1990;8:253–278. doi: 10.1146/annurev.iy.08.040190.001345. [DOI] [PubMed] [Google Scholar]
  22. Weber J., Yang J. C., Topalian S. L., Parkinson D. R., Schwartzentruber D. S., Ettinghausen S. E., Gunn H., Mixon A., Kim H., Cole D. Phase I trial of subcutaneous interleukin-6 in patients with advanced malignancies. J Clin Oncol. 1993 Mar;11(3):499–506. doi: 10.1200/JCO.1993.11.3.499. [DOI] [PubMed] [Google Scholar]
  23. Zhu Z., Tang W., Ray A., Wu Y., Einarsson O., Landry M. L., Gwaltney J., Jr, Elias J. A. Rhinovirus stimulation of interleukin-6 in vivo and in vitro. Evidence for nuclear factor kappa B-dependent transcriptional activation. J Clin Invest. 1996 Jan 15;97(2):421–430. doi: 10.1172/JCI118431. [DOI] [PMC free article] [PubMed] [Google Scholar]

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

RESOURCES