Skip to main content
SpringerLink
Log in

Rheumatoid arthritis

The role of neutrophil activation

  • Published:
Inflammation Aims and scope Submit manuscript

Abstract

Neutrophils constitute over 90% of cells found in the synovial fluid of rheumatoid arthritis (RA) patients. Since such fluids also contain immune complexes (IgG-IgG and IgG-IgM rheumatoid factors) and complement split products (C5, C5A, DES, ARG, C3B, etc.), all of the reactants are present for a local Arthus lesion. Moreover, neutrophils from RA patients endocytose these immune complexes and complement components in vivo and in vitro. In consequence, it has been suggested that lysosomal enzymes and other mediators of inflammation released by neutrophils after uptake of immune complexes (in the bulk phase or on the surface) account, at least in part, for rheumatoid inflammation. Secretion of lysosomal hydrolases, especially neutral proteases, which provoke tissue injury and generation of reactive oxygen species (e.g. O2) is part of a stimulus-secretion response to a variety of secretagogues, including immune complexes and complement components. However, the pathways of secretion and O2 generation are stimulus-specific and can be dissected to establish cause and effect relationships by (a) kinetic analysis, (b) varying the stimulus, (c) use of impermeant reagents to block discrete responses. Neutrophils also generate products of 11-cyclo-oxygenase (e.g., PGE2, TXA2) and of the 5- and 15-lipoxygenase (mono-, di-and trihetes, LTB4 and their isomers). However, the cyclo-oxygenase products (except TXA2) do not cause inflammation acting alone; indeed, they inhibit the function of neutrophils, platelets, macrophages and mast cells. The most potent proinflammatory agent yet identified as a product of arachidonate is LTB4. LTB4 is a potent Ca ionophore, a strong chemo-attractant, induces local inflammation, and activates neutrophils.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. Smolen, J. E., H. M. Korchak, andG. Weissmann. 1980. Increased levels of cyclic adenosine-3′, 5′-monophosphate in human polymorphonuclear leukocytes after surface stimulation.J. Clin. Invest. 65:1077–1085.

    Google Scholar 

  2. Cohen, H. J. andM. E. Chovaniec. 1978. Superoxide anion generation by digitonin-stimulated guinea-pig granulocytes. A basis for a continuous assay for monitoring Superoxide production and for the study of the activation of the generating systems.J. Clin. Invest. 61:1081–1087.

    Google Scholar 

  3. Smolen, J. E., H. M.Korchak, and G.Weissmann. 1983. Kinetics of degranulation of human neutrophils as measured by self-quenching of 9-aminoacridine.Biochim. Biophys. Acta (in press).

  4. Sklae, L. A., V. M. McNeil, A. J. Jesaitis, R. G. Painter, andC. G. Cochrane. 1982. A continuous, spectroscopic analysis of the kinetics of elastase secretion by neutrophils.J. Biol. Chem. 257:5471–5475.

    Google Scholar 

  5. Kaplan, H. B., H. S. Edelson, R. Freidman, andG. Weissmann. 1982. The roles of degranulation and Superoxide anion generation in neutrophil aggregation.Biochem. Biophys. Acta 721:55–63.

    Google Scholar 

  6. Sklar, L. A., Z. G. Oades, A. J. Jesaitis, R. G. Painter, andC. G. Cochrane. 1981. Fluoresceinated chemotactic peptide and high-affinity antifluorescein antibody as a probe of the temporal characteristics of neutrophil stimulation.Proc. Natl. Acad. Sci. U.S.A. 78:7540–7544.

    Google Scholar 

  7. Radin, A. R., H. M. Korchak, C. Wilkenfeld, L. E. Rutherford, andG. Weissmann. 1982. Differential requirements for receptor occupancy in neutrophil responses to a chemoattractant.Clin. Res. 30:520A.

    Google Scholar 

  8. Korchak, H. M., A. M. Rich, C. Wilkenfeld, L. E. Rutherford, andG. Weissmann, 1982. A carbocyanine dye, DiOC6(3), acts as a mitochondrial probe in human neutrophils.Biochem. Biophys. Res. Comm. 108:1495–1501.

    Google Scholar 

  9. Seligmann, B. E., E. K. Gallin, D. L. Martin, W. Shain, andJ. I. Gallin. 1980. Interaction of chemotactic factors with human polymorphonuclear leukocytes: Studies using a membrane potential sensitive cyanide dye.J. Memb. Biol. 52:257–272.

    Google Scholar 

  10. Weissmann, G., S. Hoffstein, H. Kochak, andJ. E. Smolen. 1979. The earliest membrane responses to phagocytosis: Membrane potential changes and Canloss in human granulocytes.Trans. Am. Assoc. Physicians 91:90–101.

    Google Scholar 

  11. Williams, J. A. 1980. Regulation of pancreatic acinar cell function by intracellular calcium.Am. J. Physiol. 238:G269-G279.

    Google Scholar 

  12. Douglas, W. W. 1974. Involvement of calcium in exocytosis and the exocytosisvesiculation sequence.Biochem. Soc. Symp. 39:1–28.

    Google Scholar 

  13. Putney, J. E. 1979. Stimulus-permeability coupling; role of calcium in the receptor regulation of membrane permeability.Pharmacol. Rev. 30:209–245.

    Google Scholar 

  14. Goldstein, I. M., J. K. Horn, H. B. Kaplan, andG. Weissmann. 1974. Calcium induced lysozyme secretion from human polymorphonuciear leukocytes.Biochem. Biophys. Res. Comm. 60:807–812.

    Google Scholar 

  15. O'Flaherty, J. T., H. J. Showell, E. L. Beckee, andP. A. Ward, 1978. Substances which activate neutrophils. Mechanism of action.Am. J. Path. 92:155–166.

    Google Scholar 

  16. Smith, R. J., andS. S. Iden. 1980. Properties of concanavalin A-elicited granule exocytosis from human polymorphonuclear neutrophils.Inflammation.4:343–358.

    Google Scholar 

  17. Smith, R. J., W. Wierenga, andS. Iden. 1980. Characteristics of N-fromyl-methionylleucyaphenylalanine as an inducer of lysosomal enzyme release from human neutrophils.Inflammation.4:73–88.

    Google Scholar 

  18. Smolex, J. E., H. M. Korchak, andG. Weissmann. 1981. The roles of extracellular and intraceliular calcium in lysosomal enzyme release and Superoxide anion generation by human neutrophils.Biochim. Biophys. Acta 677:512–520.

    Google Scholar 

  19. Malagodi, M. H., andC. Y. Chiou. 1974. Pharmacological evaluation of a new calcium antagonist 8-(N,N-diethyIamino)-octyl-3,4,5-trimethoxybenzoate hydrochloride (TMB-8): Studies in smooth muscle.Eur. J. Pharmacol. 27:25–33.

    Google Scholar 

  20. Naccache, P. H., H. J. Showell, E. L. Becker, andR. I. Sha'afi 1979. Changes in ionic movements across rabbit polymorphonuclear leukocyte membranes during lysosomal enzyme release.J. Cell. Biol. 75:635–664.

    Google Scholar 

  21. Korchak, H. M., S. T. Hoffstein, andG. Weissmann. 1982.In The neutrophil granules. A. M. Poisner and J. M. Trifaro, editors. The Secretory Process, Vol. 1, Elsevier Biomedical Press, New York. 317–355.

    Google Scholar 

  22. Serhan, C., H. M. Korchak, J. Broekman, J. E. Smolen, A. Marcus, andG. Weissmann. 1983. Phosphatidyl inositol breakdown and phosphatidic acid accumulation in stimulated human neutrophils: Relationship to calcium mobilization and calcium uptake.Biochim. Biophys. Acta 762:420–428.

    Google Scholar 

  23. Mottola, C., L. Dolzani, andD. Romeo. 1980. The peripheral Ca2+ pump activity of macrophages and neutrophils.Cell Calcium 1:371–379.

    Google Scholar 

  24. Volpi, M., P. H. Naccache, andR. I. Sha'afi. 1982. Preparation of inside-out membrane vesicles from neutrophils capable of actively transporting calcium.Biochem. Biophys. Res. Comm. 106:123–130.

    Google Scholar 

  25. Tsein, R. Y., T. Pozzan, andT. J. Rink. 1983. Calcium homeostasis in intact lymphocytes: Cytoplasmic free calcium monitored with a new, intracellularly trapped fluorescent indicator.J. Cell. Biol. 94:325–334.

    Google Scholar 

  26. Pozzan, T., P. D. Lew, C. G. Wollheim, andR. Y. Tsien. 1983. Monitoring cytoplasmic free calcium concentrations (Ca2+) in living polymorphonuclear leukocytes.Clin. Res. 31:320.

    Google Scholar 

  27. Lagast, H., T. Pozzan, P. D. Lew, andF. A. Waldvogel. 1983. Phorbol myristate acetate stimulates the plasma membrane pump of human and guinea pig neutrophils without raising cytoplasmic free calcium.Clin. Res. 31:410.

    Google Scholar 

  28. Sando, J. J., andM. C. Young, 1983. Identification of high-affinity phorbol ester receptorin cytosol of EL-4 thyoma cells: Requirement for calcium, magnesium, and phospholipids.Proc. Natl. Acad. Sci. U.S.A. 80:2642–2646.

    Google Scholar 

  29. Hoffstein, S. T. 1979. Ultrastructural demonstration of calcium loss from local regions of the plasma membrane of surface-stimulated human granulocytes.J. Immunol. 123:1395–1402.

    Google Scholar 

  30. Whitin, J. C., C. E. Chapman, E. R. Simons, M. E. Chovaniec, andH. J. Cohen, 1980. Correlation between membrane potential changes and Superoxide anion production in human granulocytes stimulated by phorbol myristate acetate.J. Biol. Chem. 255:1874–1878.

    Google Scholar 

  31. Naccache, P. H., J. H. Showell, E. Becker, andR. I. Sha'afi. 1979. Involvement of membrane calcium in the response of rabbit neutrophils to chemotactic factors as evidenced by the fluorescence of chlorotetracycline.J. Cell Biol. 83:179–186.

    Google Scholar 

  32. Smolen, J. E., andG. Weissmann. 1982. The effect of various stimuli and calcium antagonists on the fluorescence response of chlorotetracycline-loaded human neutrophils.Biochim. Biophys. Acta 720:172–180.

    Google Scholar 

  33. Herlin, T., C. S. Petersen, andV. Esmann. 1978. The role of calcium and cyclic adenosin3′, 5′-monophosphate in the regulation of glycogen metabolism in phagocytosing human polymorphonuclear leukocytes.Biochim. Biophys. Acta. 542:63–76.

    Google Scholar 

  34. Petersen, C. S., T. Herlin, andV. Esmann. 1978. Effects of catecholamines and glucagon on glycogen metabolism in human polymorphonuclear leukocytes.Biochim. Biophys. Acta 542:77–87.

    Google Scholar 

  35. Jackowski, S., andR. I. Sha'afi. 1979. Response of adenosine cyclic-3′, 5′-monophosphate level in rabbit neutrophiis to the chemotactic peptide formylmethionyl-leucyl-phenyalanine.Molec. Pharmacol 16:473–481.

    Google Scholar 

  36. Keller, H. U., G. Gerisch, andJ. H. Wissler. 1979. A transient rise in cyclic AMP levels following chemotactic stimulation of neutrophil granulocytes.Cell Biol. Internal. Reports 3:759–765.

    Google Scholar 

  37. Simchowitz, L., L. C. Fischbein, I. Spilberg, andJ. P. Atkinson. 1980. Induction of a transient elevation in intracellular levels of adenosine 3′, 5′-cyclic monophosphate by chemotactic factors: An early event in human neutrophil activation.J. Immunol. 124:1482–1491.

    Google Scholar 

  38. Simchowitz, L., I. Spilberg, andJ. P. Atkinson. 1983. Evidence that the functional responses of human neutrophils occur independently of transient elevations in cAMP levels.Fed. Proc. 42:1080.

    Google Scholar 

  39. Zurier, R. B., G. Weissmann, S. Hoffstein, S. Kammerman, andH. Tai 1974. Mechanisms of lysosomal enzyme release from human leukocytes II. Effects of cAMP and cGMP, autonomic agonists and agents which affect microtubule function.J. Clin. Invest. 43:297–309.

    Google Scholar 

  40. TsunG, P.-K., T. Sakamoto, andG. Weissmann. 1975. Protein kinase and phosphatases from human polymorphonuclear leukocytes.Biochem. J. 145:437–448.

    Google Scholar 

  41. Andrews, P. C., andB. M. Babior. 1983. Endogenous protein phosphorylation by resting and activated human neutrophils.Blood 61:333–340.

    Google Scholar 

  42. Huang, C. K., J. Hill, Jr.,W. M. Mackin, B. J. Bormann, andE. L. Becker. 1983. Effects of chemotactic factors on the protein phosphorylation of rabbit peritoneal neurophils.Fed. Proc. 42:1080.

    Google Scholar 

  43. Niedel, J. E., L. J. Kuhn, andG. R. Vandenbark. 1983. Phorboldiester receptor copurifies with protein kinase C.Proc. Natl. Acad. Sci. U.S.A. 80:36–40.

    Google Scholar 

  44. Serhan, C., P. Anderson, E. Goodman, P. Dunham, andG. Weissmann. 1981. Phosphatidate and oxidized fatty acids are calcium ionophors. Studies employing arsenazo III in liposomes.J. Biol. Chem 256:2736–2741.

    Google Scholar 

  45. Lee, C. W., K. F. Lewis, F. K. Austen, andE. J. Corey. 1983. Oxidative inactivation of the sulfidopeptide leukotrienes by human polymorphonuclear leukocytes (PMNs).Fed. Proc. 42:1080.

    Google Scholar 

  46. Goetzel, E. L., andW. C. Pickett. 1980.J. Immunol. 125:1789–1791.

    Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Medicine, New York University Medical Center, 550 First Avenue, 10016, New York, New York

    Gerald Weissmann

Authors
  1. Gerald Weissmann
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Helen Korchak
    View author publications

    You can also search for this author in PubMed Google Scholar

Rights and permissions

Reprints and permissions

About this article

Cite this article

Weissmann, G., Korchak, H. Rheumatoid arthritis. Inflammation 8 (Suppl 1), S3–S14 (1984). https://doi.org/10.1007/BF00915708

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1007/BF00915708

Keywords

Search

Navigation