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Effects of interleukin-6 (IL-6) and transforming growth factor-β (TGF-β) on neutrophil elastase release

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Abstract

The proinflammatory cytokine interleukin-6 (IL-6) and its potential opponent, transforming growth factor-β (TGF-β 1), have been discussed as being involved in the regulation of inflammatory processes following trauma and infections. The aim of this study was to investigate the effect of these cytokines on the regulation of neutrophil degranulation. The posttraumatic time courses of the plasma concentrations of IL-6, and the elastase-α 1-proteinase-inhibitor complex as marker of degranulation in patients undergoing severe trauma were found to be highly correlated, whereas TGF-β 1 levels were determined to be not significantly altered. The close temporal correlation of IL-6 and elastase levels could be confirmed by investigation of exudates derived from the surgical area. To prove these in vivo findings, the effect of IL-6 and TGF-β 1 on the degranulation of isolated neutrophils of healthy donors was investigated in vitro. Pathological high IL-6 concentrations were found to be capable of inducing a significant release of lysosomal elastase in a concentration-dependent manner, whereas the degranulation was unaffected by TGF-β 1. In conclusion, these data suggest an involvement of IL-6 in the regulation of neutrophil degranulation under pathological conditions. However, TGF-β 1 seems to have no direct regulatory effect besides its described chemotactic function on neutrophils.

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References

  1. Aggarwal, B. B., andE. Pocsik. 1992. Cytokines: From clone to clinic.Arch. Biochem. Biophys. 292(2):335–359.

    PubMed  Google Scholar 

  2. Billau, A., andF. Vanderkerkhove. 1991. Cytokines and their interactions with other inflammatory mediators in the pathogenesis of sepsis and septic shock.Eur. J. Clin. Invest. 21:559–573.

    PubMed  Google Scholar 

  3. Bauer, J. 1989. Interleukin-6 and its receptor during homeostasis, inflammation, and tumor growth.Klin. Wochenschr. 67:697–706.

    PubMed  Google Scholar 

  4. Hirano, T. 1992. The biology of interleukin-6.In Interleukins: Molecular Biology and Immunology. Chemical Immunology, Vol. 51. Kishimoto, editor. Karger, Basel. 153–180.

    Google Scholar 

  5. Zhou, D., A. Munster, andR. A. Winchurch. 1991. Pathologic concentrations of interleukin 6 inhibit T cell responses via induction of activation of TGF-β.FASEB J. 5:2582–2585.

    PubMed  Google Scholar 

  6. Aida, Y., andM. J. Pabst. 1991. Neutrophil responses to lipopolysaccharide. Effect of adherence on triggering and priming the respiratory burst.J. Immunol. 146(4):1271–1276.

    PubMed  Google Scholar 

  7. Kasimir, S., J. Brom, andW. König. 1991. Effect of interferon-alpha on neutrophil functions.Immunology 74:271–278.

    PubMed  Google Scholar 

  8. Baggiolini, M., P. Imboden, andP. Detmers. 1992. Neutrophil activation and effects of interleukin-8/neutrophil-activating peptide 1 (IL-8/NAP-).In Interleukin-8 (NAP-1) and Related Cytokines. Cytokines, Vol. 4. M. Baggiolini and C. Sorg, editors. Karger, Basel. 1–17.

    Google Scholar 

  9. Tennenberg, S. D. 1991. The effect of inflammatory mediators on neutrophil function.In New Aspects of Human Polymorphnuclear Leukocytes. J. Hörl and P. J. Schollmeyer, editors. Plenum Press, New York. 75–92.

    Google Scholar 

  10. Brandt, E., J. Van Damme, andH.-D. Flad. 1991. Neutrophils can generate their activator neutrophil activating peptide 2 by proteolytic cleavage of platelet-derived connective tissue-activating peptide III.Cytokine 3/4:311–321.

    Google Scholar 

  11. Porteu, F., M. Brockhaus, D. Wallach, H. Engelmann, andC. F. Nathan. 1991. Human neutrophil elastase releases a ligand-binding fragment from the 75kDa tumor necrosis factor (TNF) receptor. Comparison with the proteolytic activity responsible for shedding of TNF receptor from stimulated neutrophils.J. Biol. Chem. 266(28):18846–18853.

    PubMed  Google Scholar 

  12. Janusz, M. J., andN. S. Doherty. 1991. Degradation of cartilage matrix proteoglycan by human neutrophils involves both elastase and cathepsin G.J. Immunol. 146(11):3922–3928.

    PubMed  Google Scholar 

  13. Scuderi, P., P. A. Nez, M. L. Duerr, B. J. Wong, andC. M. Valdez. 1991. Cathepsin-G and leukocyte elastase inactivate tumor necrosis factor and lymphotoxinCell. Immunol. 135:299–313.

    PubMed  Google Scholar 

  14. Michaelis, J., M. C. M. Vissers, andC. C. Winterbourn. 1990. Human neutrophil collagenase cleavesα 1-antitrypsin.Biochem. J. 270:809–814.

    PubMed  Google Scholar 

  15. Brown, D. M., G. M. Brown, W. Macnee, andK. Donaldson. 1992. Activated human peripheral blood neutrophils produce epithelial injury and fibronectin breakdown in vitro.Inflammation 16(1):21–29.

    PubMed  Google Scholar 

  16. Jochum, M., I. Assfalg-Machleidt, D. Inthorn, D. Nast-Kolb, Ch. Waydhas, andH. Fritz. 1990. Leukozytäre Proteinasen und Hämostasestörung bei der Sepsis.In Infektion, Entzündung und Blutgerinnung. V. Tilsner and F. R. Matthias, editors. Editiones Roche, Basel. 241–254.

    Google Scholar 

  17. Tanaka, H., H. Sugimoto, T. Yoshiharu, andT. Sugimoto. 1991. Role of granulocyte elastase in tissue injury in patients with septic shock complicated by multiple-organ failure.Ann. Surg. 213(1):81–85.

    PubMed  Google Scholar 

  18. Bøyum, A. 1968. Isolation of mononuclear cells and granulocytes by one step centrifugation, and of granulocytes by combining centrifugation and sedimentation at 1g. Scand.J. Clin. Lab. Invest. 21(suppl. 97):77.

    PubMed  Google Scholar 

  19. Ohazo, H., K. Yoshizaki, N. Nishimoto, A. Ogata, H. Thago, M. Monden, M. Gotoh, T. Kishimoto, andT. Mori. 1992. Interleukin-6 as a new indicator of inflammatory status: Detection of serum levels of interleukin-6 and C-reactive protein after surgery.Surgery 111(2):201–209.

    PubMed  Google Scholar 

  20. Padova, F. D., C. Pozzi, M. J. Tondre, andR. Tritapepe. 1991. Selective and early increase of IL-1 inhibitors, IL-6 and cortisol after elective surgery.Clin Exp. Immunol. 85:137–142.

    PubMed  Google Scholar 

  21. Nuijens, J. H. E., J. J. Abbink, Y. T. Wachtvogel, R. W. Coleman, A. J. M. Eerenberg, D. Dors, A. M. J. Kamp, R. J. M. Strack van Schijndel, L. G. Thijs, andC. E. Hack. 1992. Plasma elastase-α 1-antitrypsin and lactoferrin in sepsis: Evidence for neutrophils as mediators in fatal sepsis.J. Lab. Clin. Med. 119:159–168.

    PubMed  Google Scholar 

  22. Függer, R., E. Zadrobilek, P. Götzinger, S. Klimann, M. Rogy, S. Winkler, H. Andel, M. MittelbÖck, E. Roth, F. Schulz, andA. Fritsch. 1993. Perioperative TNF-α and IL-6 concentrations correlate with septic state, organ function, and APACHE II scores in intraabdominal infection.Eur. J. Surg. 159:525–529.

    PubMed  Google Scholar 

  23. Waydhas, Ch., D. Nast-Kolb, M. Jochum, A. Trupka, S. Lenk, H. Fritz, K.-H. Duswald, andL. Schweiberer. 1992. Inflammatory mediators, infections, sepsis, and multiorgan failure in after severe trauma.Arch. Surg. 127:460–467.

    PubMed  Google Scholar 

  24. Pullicino, E. A., F. Carli, S. Poole, B. Rafferty, S. T. A. Malik, andM. Elia. 1990. The relationship between circulating concentrations of interleukin-6 (IL-6), tumor necrosis factor (TNF) and the acute phase response to elective surgery and accidental injury.Lymphokine Res. 9(2):231–238.

    PubMed  Google Scholar 

  25. Shenkin, A., W. D. Fraser, J. Series, F. P. Winstanley, A. C. McCartney, H. G. J. Burns, andJ. Van Damme. 1989. The serum interleukin-6 response to elective surgery.Lymphokine Res. 8(2): 123–127.

    PubMed  Google Scholar 

  26. Dofferhoff, A. S. M., V. J. J. Bom, H. G. De Vries-Hospers, J. Van Ingen, J. VD Meer, B. P. C. Hazenberg, P. O. M. Mulder, andJ. Weits. 1992. Patterns of cytokines, plasma endotoxin, plasminogen activator inactivator, and acute phase proteins during the treatment of severe sepsis.Crit. Care Med. 20:185–192.

    PubMed  Google Scholar 

  27. Wakefield, L. M., D. M. Smith, K. C. Flanders, andM. B. Sporn. 1988. Latent Transforming growth factor-β from human platelets. A high molecular weight complex containing precursor sequences.J. Biol. Chem. 263(16):7646–7654.

    PubMed  Google Scholar 

  28. Miyazono, K., andC. H. Heldin. 1991. Latent forms of TGF-β molecular structure and mechanisms of activation.In Clinical Applications of TGF-β. G. R. Bock and J. March, editors. John Wiley & Sons, New York.

    Google Scholar 

  29. Wahl, S. M. 1992. Transforming growth factor-β (TGF-β) in inflammation: A cause and a cure.J. Clin. Immunol. 12(2):61–74.

    PubMed  Google Scholar 

  30. Henschler, R., A. Lindermann, M. A. Brach, A. Mackensen, R. H. Mertelsmann, andF. Herrmann. 1991. Expression of functional receptors for interleukin-6 by human polymorphnuclear leucocytes.FEBS Lett. 283(1):47–51.

    PubMed  Google Scholar 

  31. Kapp, A., andG. Zeck-Kapp. 1990. Activation of the oxidative metabolism in human polymorphnuclear neutrophilic granulocytes: The role of immuno-stimulating cytokines.J. Invest. Dermatol. 95(6, suppl.):94S-99S.

    PubMed  Google Scholar 

  32. Brom, J., andW. König. 1992. Cytokine-induced (interleukins-3, -6 and -8 and tumor necrosis factor-beta) activation and deactivation of human neutrophils.Immunology 75:281–285.

    PubMed  Google Scholar 

  33. Borish, L., R. Rosenbaum, L. Albury, andS. Clark. 1989. Activation of neutrophils by recombinant interleukin-6.Cell. Immunol. 121(2):280–289.

    PubMed  Google Scholar 

  34. Henson, P. M., J. E. Henson, C. Fittschen, D. L. Bratton, andD. W. H. Riches. 1992. Degranulation and secretion by phagocytic cells.In Inflammation: Basic Principles and Clinical Correlates. J. I. Gallin, I. M. Goldstein, and R. Snyderman, editors. Raven Press, New York. 511–539.

    Google Scholar 

  35. Kuijpers, T. W., A. T. J. Toll, C. E. Van der Schoot, L. A. Ginsel, J. J. M. Onderwater, D. Roos, andA. J. Verhoeven. 1991. Membran surface antigen expression on neutrophils a reappraisal of the use of surface markers for neutrophil activation.Blood 78(4):1105–1111.

    PubMed  Google Scholar 

  36. Lipschitz, D. A., K. B. Udupa, S. R. Indelicato, andM. Das. 1991. Effect of age on second messenger generation in neutrophils.Blood 78(5):1347–1354.

    PubMed  Google Scholar 

  37. Brandes, M. E., U. E. Mai, K. Ohura, andS. M. Wahl. 1991. Type I transforming growth factor-β receptors mediate chemotaxis to transforming growth factor-β.J. Immunol. 147:1600–1606.

    PubMed  Google Scholar 

  38. Reibmann, J., S. Meixler, T. C. Lee, L. I. Gold, B. N. Cronstein, K. A. Haines, S. L. Kolanski, andG. Weissmann. 1991. Transforming growth factor-β1, a potent chemoattractant for human neutrophils, bypasses classic signal-transduction pathways.Proc. Natl. Acad. Sci. U.S.A. 88:6805–6809.

    PubMed  Google Scholar 

  39. Petersen, F., J. Van Damme, H.-D. Flad, andE. Brandt. 1991. Neutrophil activation polypeptides IL-8 and NAP-2 induce identical signal transduction pathways in the regulation of lysosomal enzyme release.Lymphokine Cytokine Res. 10(1):35–41.

    PubMed  Google Scholar 

  40. Zhou, D., A. M. Munster, andR. A. Winchurch. 1992. Inhibitory effects of interleukin-6 on immunity. Possible implications in burn patients.Arch. Surg. 127:65–69.

    PubMed  Google Scholar 

  41. Miller-Graziano, C. L., G. Szabo, K. Griffey, B. Metha, K. Kodys, andD. Catalano. 1991. Role of elevated monocyte transforming growth factorβ (TGFβ) production in post-trauma immunosuppression.J. Clin. Immunol. 11(2):95–102.

    PubMed  Google Scholar 

  42. Ogle, J. D., J. G.Noel, R. M.Sramkowsi, C. K.Ogle, and W. J.Alexander. Effects of combination of tumor necrosis factor alpha and chemotactic peptide f-Met-Leu-Phe, on phagocytosis of opsonized microspheres by human neutrophils.Inflammation 16(1):57–68.

  43. Yuo, A., S. Kitagawa, T. Kasahara, K. Matsushima, M. Saito, andF. Takaku. 1991. Stimulation and priming of human neutrophils by interleukin-8: Cooperation with tumor necrosis factor and colony-stimulating factors.Blood 78(10):2708–2714.

    PubMed  Google Scholar 

  44. Elbim, C., S. Chollet-Martin, S. Bailly, J. Hakim, andM.-A. Gouregot-Pocidalo. 1993. Priming of polymorphnuclear neutrophils by tumor necrosis factorα in whole blood: Identification of two polymorphnuclear neutrophils subpopulation in response to formyl-peptides.Blood 82(2):633–640.

    PubMed  Google Scholar 

  45. Tennenberg, D., M. J. Jacobs, andJ. S. Solomkin. 1987. Complement-mediated neutrophil activation in sepsis- and trauma adult respiratory distress synchrome: Clarification with radioaerosol lung scans.Arch. Surg. 122:26.

    PubMed  Google Scholar 

  46. Cicco, N. A., A. Lindemann, J. Content, P. Vandenbussche, M. Lübbert, J. Gauss, R. Mertelsmann, andF. Herrmann. 1990. Inducible production of Interleukin-6 by human polymorphnuclear neutrophils: Role of granulocyte-macrophage colony-stimulating factor and tumor necrosis factor-alpha.Blood 75(10):2049–2052.

    PubMed  Google Scholar 

  47. Lloyd, A. R., andJ. J. Oppenheim. 1992. Poly's lament: the neglected role of the polymorphnuclear neutrophil in the afferent limb of the immune response.Immunol. Today 13(5):169–172.

    PubMed  Google Scholar 

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Authors and Affiliations

  1. Division of Experimental Internal Medicine, Center of Internal Medicine, Germany

    U. Bank, D. Reinhold & S. Ansorge

  2. Department of Clinical Chemistry, Otto von Guericke University Magdeburg, Medical School, Leipziger Strasse 44, 39120, Magdeburg, Germany

    D. Kunz

  3. Department of Surgery, Germany

    H. -U. Schulz

  4. Department of Anesthesiology and Intensive Care Medicine, Germany

    Ch. Schneemilch & W. Brandt

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Bank, U., Reinhold, D., Kunz, D. et al. Effects of interleukin-6 (IL-6) and transforming growth factor-β (TGF-β) on neutrophil elastase release. Inflammation 19, 83–99 (1995). https://doi.org/10.1007/BF01534383

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