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Sympathetic activation triggers systemic interleukin-10 release in immunodepression induced by brain injury

Abstract

The mechanism of immunodepression after brain injury is not yet clear. Here we demonstrate rapid systemic release of the immunoinhibitory cytokine interleukin-10, monocytic deactivation and a high incidence of infection in patients with ‘sympathetic storm’ due to acute accidental or iatrogenic brain trauma. In vitro studies showed that within minutes catecholamines trigger the secretion of interleukin-10 from unstimulated monocytes through a β-adrenoreceptor-mediated, cAMP/protein kinase A-dependent pathway. We found that in a rat model of acute brain injury, the βreceptor antagonist propranolol prevented the increase of interleukin-10 plasma levels. Rapid monocytic interleukin-10 release after sympathetic activation may represent a common pathway for immunodepression induced by stress and injury.

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References

  1. Rodriguez, J.L. et al. Pneumonia: incidence, risk factors, and outcome in injured patients. I. Trauma. 31, 907–912 (1991).

    Article  CAS  Google Scholar 

  2. Hsieh, A.H., Bishop, M.J., Kubilis, P.S., Newell, D.W. & Pierson, D.J. Pneumonia following closed head injury. Am. Rev. Respir. Dis. 146, 290–294 (1992).

    Article  CAS  Google Scholar 

  3. Jarek, M.J., Legare, E.J., McDermott, M.T., Merenich, J.A. & Kollef, M.H. Endocrine profiles for outcome prediction from the intensive care unit. Crit. Care Med. 21, 543–550 (1993).

    Article  CAS  Google Scholar 

  4. Chiolero, R. & Berger, M. Endocrine response to brain injury. New Horiz. 2, 432–442 (1994).

    CAS  PubMed  Google Scholar 

  5. Rothwell, P.M. & Lawler, P.G. Prediction of outcome in intensive care patients using endocrine parameters [see comments]. Crit. Care Med. 23, 78–83 (1995).

    Article  CAS  Google Scholar 

  6. Kapcala, L.P., Chautard, T. & Eskay, R.L. The protective role of the hypothalamic-pituitary-adrenal axis against lethality produced by immune, infectious, and inflammatory stress. Ann. NY Acad. Sci. 771, 419–437 (1995).

    Article  CAS  Google Scholar 

  7. Adcock, I.M. et al. Effects of glucocorticoids on transcription factor activation in human peripheral blood mononuclear cells. Am. J. Physiol. 268, C331–8 (1995).

    Article  CAS  Google Scholar 

  8. Sternberg, E.M. Neuroendocrine factors in susceptibility to inflammatory disease: focus on the hypothalamic-pituitary-adrenal axis. Horm. Res. 43, 159–161 (1995).

    Article  CAS  Google Scholar 

  9. Koff, W.C. Fann, A.V., Dunegan, M. A. & Lachman, L. B. Catecholamine-induced suppression of interleukin-1 production. Lymphokine Res. 5, 239–247 (1986).

    CAS  PubMed  Google Scholar 

  10. van der Poll, T., Coyle, S. M., Barbosa, K., Braxton, C.C. & Lowry, S. F. Epinephrine inhibits tumor necrosis factor-alpha and potentiates interleukin 10 production during human endotoxemia. J. Clin. Invest. 97, 713–719 (1996).

    Article  CAS  Google Scholar 

  11. Elenkov, I.J., Papanicolaou, D. A., Wilder, R. L. & Chrousos, G. P. Modulatory effects of glucocorticoids and catecholamines on human interleukin-12 and interleukin-10 production: clinical implications. Proc. Assoc. Am. Physicians. 108, 374–381 (1996).

    CAS  PubMed  Google Scholar 

  12. Gibbons, R. A., Martinez, O. M., Lim, R. C., Horn, J. K. & Garovoy, M. R. Reduction in HLA-DR, HLA-DQ and HLA-DP expression by Leu-M3+ cells from the peripheral blood of patients with thermal injury. Clin. Exp. Immunol. 75, 371–375 (1989).

    CAS  PubMed  PubMed Central  Google Scholar 

  13. Guillou, P. J. Biological variation in the development of sepsis after surgery or trauma. Lancet 342, 217–220 (1993).

    Article  CAS  Google Scholar 

  14. Livingston, D. H., Appel, S. H., Wellhausen, S. R., Sonnenfeld, G. & Polk, H. C. Jr. Depressed interferon gamma production and monocyte HLA-DR expression after severe injury. Arch. Surg. 123, 1309–1312 (1988).

    Article  CAS  Google Scholar 

  15. Asadullah, K. et al. Very low monocytic HLA-DR expression indicates high risk of infection - Immunomonitoring for patients after neurosurgery and patients during high dose steroid therapy. Eur. J. Emergency Med. 2, 184–190 (1995).

    Article  CAS  Google Scholar 

  16. Döcke, W. D. et al. in 4th International Congress on The Immune Consequences of Trauma, Shock and Sepsis - Mechanisms and Therapeutic Approaches. (eds. Faist, E., Baue, A.E. & Schildberg, F.W.) 293–298 (Monduzzi Editore, Bologna, ltaly, 1997).

    Google Scholar 

  17. Volk, H. D. et al. Diagnostic value of an immune monitoring program for the clinical management of immunosuppressed patients with septic complications. Clin. Transplant. 3, 246–252 (1989).

    Google Scholar 

  18. Volk, H. D. et al. Monocyte deactivation - rationale for a new therapeutic strategy in sepsis. Intensive. Care Med. 22 Suppl 4, S474–81 (1996).

    Article  Google Scholar 

  19. Döcke, W. D. et al. Monocyte deactivation in septic patients: restoration by IFN-gamma treatment. Nature Med 3, 678–681 (1997).

    Article  Google Scholar 

  20. Randow, F. et al. Mechanism of endotoxin desensitization: involvement of interleukin 10 and transforming growth factor beta. J. Exp. Med. 181, 1887–1892 (1995).

    Article  CAS  Google Scholar 

  21. Moore, K. W., O'Garra, A., de Waal Malefyt, R., Vieira, P. & Mosmann, T. R. Interleukin-10. Annu. Rev. Immunol. 11, 165–190 (1993).

    Article  CAS  Google Scholar 

  22. Asadullah, K. et al. Immunodepression following neurosurgical procedures. Crit. Care Med. 23, 1976–1983 (1995).

    Article  CAS  Google Scholar 

  23. Bone, R. C. Sir Isaac Newton, sepsis, SIRS, and CARS. Crit. Care Med. 24, 1125–1128 (1996).

    Article  CAS  Google Scholar 

  24. Platzer, C., Meisel, C. Vogt, K., Platzer, M. & Volk, H. D. Up-regulation of monocytic IL-10 by tumor necrosis factor-alpha and CAMP elevating drugs. Int. Immunol. 7, 517–523 (1995).

    Article  CAS  Google Scholar 

  25. Wanidworanun, C. & Strober, W. Predominant role of tumor necrosis factor-alpha in human monocyte IL-10 synthesis. J. Immunol. 151, 6853–6861 (1993).

    CAS  PubMed  Google Scholar 

  26. Dinarello, C. A. & Thompson, R. C. Blocking IL-1: interleukin 1 receptor antagonist in vivo and in vitro. Immunol. Today 12, 404–410 (1991).

    Article  CAS  Google Scholar 

  27. Heesen, M. et al. Increase of interleukin-6 plasma levels after elective craniotomy: influence of interleukin-10 and catecholamines. Acta Neurochir. Wien. 138, 77–80 (1996).

    Article  CAS  Google Scholar 

  28. Suberville, S. et al. Regulation of interleukin-10 production by beta-adrenergic agonists. Eur. I. Immunol. 26, 2601–2605 (1996).

    Article  CAS  Google Scholar 

  29. Uottla, P. The role of cyclic AMP and oxygen intermediates in the inhibition of cellular immunity in cancer. Cancer Immunol. Immunother. 43, 1 –9 (1996).

    Article  Google Scholar 

  30. Szabo, C. et al. Isoproterenol regulates tumour necrosis factor, interleukin-10, interleukin-6 and nitric oxide production and protects against the development of vascular hyporeactivity in endotoxaemia. Immunology 90, 95–100 (1997).

    Article  CAS  Google Scholar 

  31. Karlsberg, R. P., Cryer, P. E. & Roberts, R. Serial plasma catecholamine response early in the course of clinical acute myocardial infarction: relationship to infarct extent and mortality. Am. Heart J. 102, 24–29 (1981).

    Article  CAS  Google Scholar 

  32. Döcke, W. D. et al. Rapid IL-10 release and signs for immunodepression after acute myocardial infarction. Crit. Care Med. 25, A50 (Abstract) (1997).

    Google Scholar 

  33. Hahn, P. Y. et al. Sustained elevation in circulating catecholamine levels during polymicrobial sepsis. Shock 4, 269–273 (1995).

    Article  CAS  Google Scholar 

  34. Naito, Y. et al. Responses of plasma adrenocorticotropic hormone, cortisol, and cytokines during and after upper abdominal surgery. Anesthesiology 77, 426–431 (1992).

    Article  CAS  Google Scholar 

  35. Fabian, T. C. et al. Reduced tumor necrosis factor production in endotoxin-spiked whole blood after trauma: experimental results and clinical correlation. Surgery 118, 63–72 (1995).

    Article  CAS  Google Scholar 

  36. Sherry, R. M., Cue, J. I., Goddard, J. K., Parramore, J. B. & DiPiro, J. T. Interleukin-10 is associated with the development of sepsis in trauma patients. J. Trauma. 40, 613–616 (1996).

    Article  CAS  Google Scholar 

  37. Dunn, A. J. Infection as a stressor: a cytokine-mediated activation of the hypothal-amopituitary-adrenal axis? Ciba. Found. Symp. 172, 226–239 (1993).

    CAS  PubMed  Google Scholar 

  38. Cheng, G. J., Morrow Tesch, J. L., Beller, D. I., Levy, E. M. & Black, P. H. Immunosuppression in mice induced by cold water stress. Brain Behav. Immun. 4, 278–291 (1990).

    Article  CAS  Google Scholar 

  39. Zwilling, B. S., Brown, D., Feng, N., Sheridan, J. & Pearl, D. The effect of adrenalectomy on the restraint stress induced suppression of MHC class II expression by murine peritoneal macrophages. Brain Behav. lmmun. 7, 29–35 (1993).

    Article  CAS  Google Scholar 

  40. Dobbin, J. P., Harth, M., McCain, G. A., Martin, R. A. & Cousin, K. Cytokine production and lymphocyte transformation during stress. Brain Behav. Immun. 5, 339–348 (1991).

    Article  CAS  Google Scholar 

  41. Zorrilla, E. P., Redei, E. & DeRubeis, R. J. Reduced cytokine levels and T-cell function in healthy males: relation to individual differences in subclinical anxiety. Brain Behav. lmmun. 8, 293–312 (1994).

    Article  CAS  Google Scholar 

  42. justice, B. Critical life events and the onset of illness. Compr. Ther. 20, 232–238 (1994).

    CAS  PubMed  Google Scholar 

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Woiciechowsky, C., Asadullah, K., Nestler, D. et al. Sympathetic activation triggers systemic interleukin-10 release in immunodepression induced by brain injury. Nat Med 4, 808–813 (1998). https://doi.org/10.1038/nm0798-808

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