Human metapneumovirus inhibits the IL-6-induced JAK/STAT3 signalling cascade in airway epithelium Free

Abstract

The host cytokine IL-6 plays an important role in host defence and prevention of lung injury from various pathogens, making IL-6 an important mediator in the host’s susceptibility to respiratory infections. The cellular response to IL-6 is mediated through a Janus kinase/signal transducer and activator of transcription 3 (JAK/STAT3) signal transduction pathway. Human metapneumovirus (hMPV) is an important causative agent of viral respiratory infections known to inhibit the IFN-mediated activation of STAT1. However, little is known about the interactions between this virus and other STAT signalling cascades. Herein, we showed that hMPV can attenuate the IL-6-mediated JAK/STAT3 signalling cascade in lung epithelial cells. HMPV inhibited a key event in this pathway by impeding the phosphorylation and nuclear translocation of STAT3 in A549 cells and in primary normal human bronchial epithelial cells. Further studies established that hMPV interrupted the IL-6-induced JAK/STAT pathway early in the signal transduction pathway by blocking the phosphorylation of JAK2. By antagonizing the IL-6-mediated JAK/STAT3 pathway, hMPV perturbed the expression of IL-6-inducible genes important for apoptosis, cell differentiation and growth. Infection with hMPV also differentially regulated the effects of IL-6 on apoptosis. Thus, hMPV regulation of these genes could usurp the protective roles of IL-6, and these data provide insight into an important element of viral pathogenesis.

Loading

Article metrics loading...

/content/journal/jgv/10.1099/vir.0.055632-0
2014-01-01
2024-03-28
Loading full text...

Full text loading...

/deliver/fulltext/jgv/95/1/26.html?itemId=/content/journal/jgv/10.1099/vir.0.055632-0&mimeType=html&fmt=ahah

References

  1. Abu-Ghazaleh R., Kabir J., Jia H., Lobo M., Zachary I. 2001; Src mediates stimulation by vascular endothelial growth factor of the phosphorylation of focal adhesion kinase at tyrosine 861, and migration and anti-apoptosis in endothelial cells. Biochem J 360:255–264 [View Article][PubMed]
    [Google Scholar]
  2. Akbar A. N., Borthwick N. J., Wickremasinghe R. G., Panayoitidis P., Pilling D., Bofill M., Krajewski S., Reed J. C., Salmon M. 1996; Interleukin-2 receptor common gamma-chain signaling cytokines regulate activated T cell apoptosis in response to growth factor withdrawal: selective induction of anti-apoptotic (bcl-2, bcl-xL ) but not pro-apoptotic (bax, bcl-xS ) gene expression. Eur J Immunol 26:294–299 [View Article][PubMed]
    [Google Scholar]
  3. Allen D. L., Unterman T. G. 2007; Regulation of myostatin expression and myoblast differentiation by FoxO and SMAD transcription factors. Am J Physiol Cell Physiol 292:C188–C199 [View Article][PubMed]
    [Google Scholar]
  4. Alvarez R., Harrod K. S., Shieh W. J., Zaki S., Tripp R. A. 2004; Human metapneumovirus persists in BALB/c mice despite the presence of neutralizing antibodies. J Virol 78:14003–14011 [View Article][PubMed]
    [Google Scholar]
  5. Aujla S. J., Kolls J. K. 2009; IL-22: a critical mediator in mucosal host defense. J Mol Med (Berl) 87:451–454 [View Article][PubMed]
    [Google Scholar]
  6. Best S. M., Morris K. L., Shannon J. G., Robertson S. J., Mitzel D. N., Park G. S., Boer E., Wolfinbarger J. B., Bloom M. E. 2005; Inhibition of interferon-stimulated JAK-STAT signaling by a tick-borne flavivirus and identification of NS5 as an interferon antagonist. J Virol 79:12828–12839 [View Article][PubMed]
    [Google Scholar]
  7. Bitko V., Shulyayeva O., Mazumder B., Musiyenko A., Ramaswamy M., Look D. C., Barik S. 2007; Nonstructural proteins of respiratory syncytial virus suppress premature apoptosis by an NF-κB-dependent, interferon-independent mechanism and facilitate virus growth. J Virol 81:1786–1795 [View Article][PubMed]
    [Google Scholar]
  8. Cacalano N. A., Sanden D., Johnston J. A. 2001; Tyrosine-phosphorylated SOCS-3 inhibits STAT activation but binds to p120 RasGAP and activates Ras. Nat Cell Biol 3:460–465 [View Article][PubMed]
    [Google Scholar]
  9. DiCosmo B. F., Geba G. P., Picarella D., Elias J. A., Rankin J. A., Stripp B. R., Whitsett J. A., Flavell R. A. 1994; Airway epithelial cell expression of interleukin-6 in transgenic mice. Uncoupling of airway inflammation and bronchial hyperreactivity. J Clin Invest 94:2028–2035 [View Article][PubMed]
    [Google Scholar]
  10. Dinwiddie D. L., Harrod K. S. 2008; Human metapneumovirus inhibits IFN-α signaling through inhibition of STAT1 phosphorylation. Am J Respir Cell Mol Biol 38:661–670 [View Article][PubMed]
    [Google Scholar]
  11. Ebihara T., Endo R., Kikuta H., Ishiguro N., Yoshioka M., Ma X., Kobayashi K. 2003; Seroprevalence of human metapneumovirus in Japan. J Med Virol 70:281–283 [View Article][PubMed]
    [Google Scholar]
  12. Ebihara T., Endo R., Kikuta H., Ishiguro N., Ishiko H., Hara M., Takahashi Y., Kobayashi K. 2004; Human metapneumovirus infection in Japanese children. J Clin Microbiol 42:126–132 [View Article][PubMed]
    [Google Scholar]
  13. Edwards K. M., Zhu Y., Griffin M. R., Weinberg G. A., Hall C. B., Szilagyi P. G., Staat M. A., Iwane M., Prill M. M., Williams J. V. New Vaccine Surveillance Network 2013; Burden of human metapneumovirus infection in young children. N Engl J Med 368:633–643 [View Article][PubMed]
    [Google Scholar]
  14. Ghoshal K., Majumder S., Zhu Q., Hunzeker J., Datta J., Shah M., Sheridan J. F., Jacob S. T. 2001; Influenza virus infection induces metallothionein gene expression in the mouse liver and lung by overlapping but distinct molecular mechanisms. Mol Cell Biol 21:8301–8317 [View Article][PubMed]
    [Google Scholar]
  15. Greensill J., McNamara P. S., Dove W., Flanagan B., Smyth R. L., Hart C. A. 2003; Human metapneumovirus in severe respiratory syncytial virus bronchiolitis. Emerg Infect Dis 9:372–375 [View Article][PubMed]
    [Google Scholar]
  16. Groskreutz D. J., Monick M. M., Yarovinsky T. O., Powers L. S., Quelle D. E., Varga S. M., Look D. C., Hunninghake G. W. 2007; Respiratory syncytial virus decreases p53 protein to prolong survival of airway epithelial cells. J Immunol 179:2741–2747 [View Article][PubMed]
    [Google Scholar]
  17. Guerrero-Plata A., Casola A., Garofalo R. P. 2005; Human metapneumovirus induces a profile of lung cytokines distinct from that of respiratory syncytial virus. J Virol 79:14992–14997 [View Article][PubMed]
    [Google Scholar]
  18. Heinrich P. C., Behrmann I., Müller-Newen G., Schaper F., Graeve L. 1998; Interleukin-6-type cytokine signalling through the gp130/Jak/STAT pathway. Biochem J 334:297–314[PubMed]
    [Google Scholar]
  19. Horvath C. M. 2004; Silencing STATs: lessons from paramyxovirus interferon evasion. Cytokine Growth Factor Rev 15:117–127 [View Article][PubMed]
    [Google Scholar]
  20. Huang W. L., Yeh H. H., Lin C. C., Lai W. W., Chang J. Y., Chang W. T., Su W. C. 2010; Signal transducer and activator of transcription 3 activation up-regulates interleukin-6 autocrine production: a biochemical and genetic study of established cancer cell lines and clinical isolated human cancer cells. Mol Cancer 9:309 [View Article][PubMed]
    [Google Scholar]
  21. Huck B., Neumann-Haefelin D., Schmitt-Graeff A., Weckmann M., Mattes J., Ehl S., Falcone V. 2007; Human metapneumovirus induces more severe disease and stronger innate immune response in BALB/c mice as compared with respiratory syncytial virus. Respir Res 8:6 [View Article][PubMed]
    [Google Scholar]
  22. Itoh M., Hotta H., Homma M. 1998; Increased induction of apoptosis by a Sendai virus mutant is associated with attenuation of mouse pathogenicity. J Virol 72:2927–2934[PubMed]
    [Google Scholar]
  23. Jones M. R., Quinton L. J., Simms B. T., Lupa M. M., Kogan M. S., Mizgerd J. P. 2006; Roles of interleukin-6 in activation of STAT proteins and recruitment of neutrophils during Escherichia coli pneumonia. J Infect Dis 193:360–369 [View Article][PubMed]
    [Google Scholar]
  24. Kamimura D., Ishihara K., Hirano T. 2003; IL-6 signal transduction and its physiological roles: the signal orchestration model. Rev Physiol Biochem Pharmacol 149:1–38 [View Article][PubMed]
    [Google Scholar]
  25. Karni R., Jove R., Levitzki A. 1999; Inhibition of pp60c-Src reduces Bcl-XL expression and reverses the transformed phenotype of cells overexpressing EGF and HER-2 receptors. Oncogene 18:4654–4662 [View Article][PubMed]
    [Google Scholar]
  26. Ke Z., Zhang X., Ma L., Wang L. 2008; Deleted in pancreatic carcinoma locus 4/Smad4 participates in the regulation of apoptosis by affecting the Bcl-2/Bax balance in non-small cell lung cancer. Hum Pathol 39:1438–1445 [View Article][PubMed]
    [Google Scholar]
  27. Kida H., Yoshida M., Hoshino S., Inoue K., Yano Y., Yanagita M., Kumagai T., Osaki T., Tachibana I. other authors 2005; Protective effect of IL-6 on alveolar epithelial cell death induced by hydrogen peroxide. Am J Physiol Lung Cell Mol Physiol 288:L342–L349 [View Article][PubMed]
    [Google Scholar]
  28. Kleinsteuber K., Heesch K., Schattling S., Sander-Juelch C., Mock U., Riecken K., Fehse B., Fleischer B., Jacobsen M. 2012; SOCS3 promotes interleukin-17 expression of human T cells. Blood 120:4374–4382 [View Article][PubMed]
    [Google Scholar]
  29. Kotelkin A., Prikhod’ko E. A., Cohen J. I., Collins P. L., Bukreyev A. 2003; Respiratory syncytial virus infection sensitizes cells to apoptosis mediated by tumor necrosis factor-related apoptosis-inducing ligand. J Virol 77:9156–9172 [View Article][PubMed]
    [Google Scholar]
  30. Kuiken T., van den Hoogen B. G., van Riel D. A., Laman J. D., van Amerongen G., Sprong L., Fouchier R. A., Osterhaus A. D. 2004; Experimental human metapneumovirus infection of cynomolgus macaques (Macaca fascicularis) results in virus replication in ciliated epithelial cells and pneumocytes with associated lesions throughout the respiratory tract. Am J Pathol 164:1893–1900 [View Article][PubMed]
    [Google Scholar]
  31. Ladel C. H., Blum C., Dreher A., Reifenberg K., Kopf M., Kaufmann S. H. 1997; Lethal tuberculosis in interleukin-6-deficient mutant mice. Infect Immun 65:4843–4849[PubMed]
    [Google Scholar]
  32. Laham F. R., Israele V., Casellas J. M., Garcia A. M., Lac Prugent C. M., Hoffman S. J., Hauer D., Thumar B., Name M. I. other authors 2004; Differential production of inflammatory cytokines in primary infection with human metapneumovirus and with other common respiratory viruses of infancy. J Infect Dis 189:2047–2056 [View Article][PubMed]
    [Google Scholar]
  33. Leung J., Esper F., Weibel C., Kahn J. S. 2005; Seroepidemiology of human metapneumovirus (hMPV) on the basis of a novel enzyme-linked immunosorbent assay utilizing hMPV fusion protein expressed in recombinant vesicular stomatitis virus. J Clin Microbiol 43:1213–1219 [View Article][PubMed]
    [Google Scholar]
  34. Li Q., Wu L., Oelschlager D. K., Wan M., Stockard C. R., Grizzle W. E., Wang N., Chen H., Sun Y., Cao X. 2005; Smad4 inhibits tumor growth by inducing apoptosis in estrogen receptor-α-positive breast cancer cells. J Biol Chem 280:27022–27028 [View Article][PubMed]
    [Google Scholar]
  35. Liu T., Castro S., Brasier A. R., Jamaluddin M., Garofalo R. P., Casola A. 2004; Reactive oxygen species mediate virus-induced STAT activation: role of tyrosine phosphatases. J Biol Chem 279:2461–2469 [View Article][PubMed]
    [Google Scholar]
  36. Liu Y., Haas D. L., Poore S., Isakovic S., Gahan M., Mahalingam S., Fu Z. F., Tripp R. A. 2009; Human metapneumovirus establishes persistent infection in the lungs of mice and is reactivated by glucocorticoid treatment. J Virol 83:6837–6848 [View Article][PubMed]
    [Google Scholar]
  37. Lu Y., Fukuyama S., Yoshida R., Kobayashi T., Saeki K., Shiraishi H., Yoshimura A., Takaesu G. 2006; Loss of SOCS3 gene expression converts STAT3 function from anti-apoptotic to pro-apoptotic. J Biol Chem 281:36683–36690 [View Article][PubMed]
    [Google Scholar]
  38. Madonna S., Scarponi C., Pallotta S., Cavani A., Albanesi C. 2012; Anti-apoptotic effects of suppressor of cytokine signaling 3 and 1 in psoriasis. Cell Death Dis 3:e334 [View Article][PubMed]
    [Google Scholar]
  39. Martinello R. A., Esper F., Weibel C., Ferguson D., Landry M. L., Kahn J. S. 2006; Human metapneumovirus and exacerbations of chronic obstructive pulmonary disease. J Infect 53:248–254 [View Article][PubMed]
    [Google Scholar]
  40. Matsuzaki Y., Xu Y., Ikegami M., Besnard V., Park K. S., Hull W. M., Wert S. E., Whitsett J. A. 2006; Stat3 is required for cytoprotection of the respiratory epithelium during adenoviral infection. J Immunol 177:527–537[PubMed] [CrossRef]
    [Google Scholar]
  41. Moodley Y. P., Misso N. L., Scaffidi A. K., Fogel-Petrovic M., McAnulty R. J., Laurent G. J., Thompson P. J., Knight D. A. 2003; Inverse effects of interleukin-6 on apoptosis of fibroblasts from pulmonary fibrosis and normal lungs. Am J Respir Cell Mol Biol 29:490–498 [View Article][PubMed]
    [Google Scholar]
  42. Murphy E. A., Davis J. M., Brown A. S., Carmichael M. D., Ghaffar A., Mayer E. P. 2008; Effect of IL-6 deficiency on susceptibility to HSV-1 respiratory infection and intrinsic macrophage antiviral resistance. J Interferon Cytokine Res 28:589–595 [View Article][PubMed]
    [Google Scholar]
  43. Palosaari H., Parisien J. P., Rodriguez J. J., Ulane C. M., Horvath C. M. 2003; STAT protein interference and suppression of cytokine signal transduction by measles virus V protein. J Virol 77:7635–7644 [View Article][PubMed]
    [Google Scholar]
  44. Quinton L. J., Jones M. R., Robson B. E., Simms B. T., Whitsett J. A., Mizgerd J. P. 2008; Alveolar epithelial STAT3, IL-6 family cytokines, and host defense during Escherichia coli pneumonia. Am J Respir Cell Mol Biol 38:699–706 [View Article][PubMed]
    [Google Scholar]
  45. Renauld J. C., Vink A., Louahed J., Van Snick J. 1995; Interleukin-9 is a major anti-apoptotic factor for thymic lymphomas. Blood 85:1300–1305[PubMed]
    [Google Scholar]
  46. Rossa C. Jr, Sommer G., Spolidorio L. C., Rosenzweig S. A., Watson D. K., Kirkwood K. L. 2012; Loss of expression and function of SOCS3 is an early event in HNSCC: altered subcellular localization as a possible mechanism involved in proliferation, migration and invasion. PLoS ONE 7:e45197 [View Article][PubMed]
    [Google Scholar]
  47. Schmidt S., Rainer J., Ploner C., Presul E., Riml S., Kofler R. 2004; Glucocorticoid-induced apoptosis and glucocorticoid resistance: molecular mechanisms and clinical relevance. Cell Death Differ 11:Suppl 1S45–S55 [View Article][PubMed]
    [Google Scholar]
  48. Teodoro J. G., Branton P. E. 1997; Regulation of apoptosis by viral gene products. J Virol 71:1739–1746[PubMed]
    [Google Scholar]
  49. Todaro M., Lombardo Y., Francipane M. G., Alea M. P., Cammareri P., Iovino F., Di Stefano A. B., Di Bernardo C., Agrusa A. other authors 2008; Apoptosis resistance in epithelial tumors is mediated by tumor-cell-derived interleukin-4. Cell Death Differ 15:762–772 [View Article][PubMed]
    [Google Scholar]
  50. Ulane C. M., Rodriguez J. J., Parisien J. P., Horvath C. M. 2003; STAT3 ubiquitylation and degradation by mumps virus suppress cytokine and oncogene signaling. J Virol 77:6385–6393 [View Article][PubMed]
    [Google Scholar]
  51. Ungefroren H., Groth S., Sebens S., Lehnert H., Gieseler F., Fändrich F. 2011; Differential roles of Smad2 and Smad3 in the regulation of TGF-β1-mediated growth inhibition and cell migration in pancreatic ductal adenocarcinoma cells: control by Rac1. Mol Cancer 10:67 [View Article][PubMed]
    [Google Scholar]
  52. van den Hoogen B. G., de Jong J. C., Groen J., Kuiken T., de Groot R., Fouchier R. A., Osterhaus A. D. 2001; A newly discovered human pneumovirus isolated from young children with respiratory tract disease. Nat Med 7:719–724 [View Article][PubMed]
    [Google Scholar]
  53. van der Poll T., Keogh C. V., Guirao X., Buurman W. A., Kopf M., Lowry S. F. 1997; Interleukin-6 gene-deficient mice show impaired defense against pneumococcal pneumonia. J Infect Dis 176:439–444 [View Article][PubMed]
    [Google Scholar]
  54. Ward N. S., Waxman A. B., Homer R. J., Mantell L. L., Einarsson O., Du Y., Elias J. A. 2000; Interleukin-6-induced protection in hyperoxic acute lung injury. Am J Respir Cell Mol Biol 22:535–542 [View Article][PubMed]
    [Google Scholar]
  55. Waxman A. B., Mahboubi K., Knickelbein R. G., Mantell L. L., Manzo N., Pober J. S., Elias J. A. 2003; Interleukin-11 and interleukin-6 protect cultured human endothelial cells from H2O2-induced cell death. Am J Respir Cell Mol Biol 29:513–522 [View Article][PubMed]
    [Google Scholar]
  56. Welliver R. C. Sr 2008; The immune response to respiratory syncytial virus infection: friend or foe?. Clin Rev Allergy Immunol 34:163–173 [View Article][PubMed]
    [Google Scholar]
  57. Whittington H. A., Armstrong L., Uppington K. M., Millar A. B. 2004; Interleukin-22: a potential immunomodulatory molecule in the lung. Am J Respir Cell Mol Biol 31:220–226 [View Article][PubMed]
    [Google Scholar]
  58. Williams J. V., Harris P. A., Tollefson S. J., Halburnt-Rush L. L., Pingsterhaus J. M., Edwards K. M., Wright P. F., Crowe J. E. Jr 2004; Human metapneumovirus and lower respiratory tract disease in otherwise healthy infants and children. N Engl J Med 350:443–450 [View Article][PubMed]
    [Google Scholar]
  59. Yu M., Zheng X., Witschi H., Pinkerton K. E. 2002; The role of interleukin-6 in pulmonary inflammation and injury induced by exposure to environmental air pollutants. Toxicol Sci 68:488–497 [View Article][PubMed]
    [Google Scholar]
  60. Zhang J., Kalyankrishna S., Wislez M., Thilaganathan N., Saigal B., Wei B., Ma L., Wistuba II, Johnson F. M. other authors 2007; SRC-family kinases are activated in non-small cell lung cancer and promote the survival of epidermal growth factor receptor-dependent cell lines. Am J Pathol 170:366–376[PubMed] [CrossRef]
    [Google Scholar]
  61. Zhang X., Yin P., Di D., Luo G., Zheng L., Wei J., Zhang J., Shi Y., Zhang J., Xu N. 2009; IL-6 regulates MMP-10 expression via JAK2/STAT3 signaling pathway in a human lung adenocarcinoma cell line. Anticancer Res 29:4497–4501[PubMed]
    [Google Scholar]
  62. Zhang X., Goel T., Goodfield L. L., Muse S. J., Harvill E. T. 2011; Decreased leukocyte accumulation and delayed Bordetella pertussis clearance in IL-6-/- mice. J Immunol 186:4895–4904 [View Article][PubMed]
    [Google Scholar]
http://instance.metastore.ingenta.com/content/journal/jgv/10.1099/vir.0.055632-0
Loading
/content/journal/jgv/10.1099/vir.0.055632-0
Loading

Data & Media loading...

Supplements

Supplementary material 1

PDF

Most cited Most Cited RSS feed