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The Journal of Clinical Investigation logoLink to The Journal of Clinical Investigation
. 1992 Jun;89(6):1734–1740. doi: 10.1172/JCI115775

Dynamics of the cellular and humoral components of the inflammatory response elicited in skin blisters in humans.

D B Kuhns 1, E DeCarlo 1, D M Hawk 1, J I Gallin 1
PMCID: PMC295861  PMID: 1601984

Abstract

Skin blisters induced by suction on the forearm of normal volunteers provide a convenient model to study the inflammatory response in vivo in man. In our study, after removal of the roof of the blister, i.e., the epidermis, the exposed floor of the blister (dermal-epidermal interface) was bathed with 70% autologous serum using a multiwell skin chamber. Migration of leukocytes (90-95% neutrophils) into the chamber fluid was detectable within 3 h, and appeared to plateau at 16-24 h. Sampling of the dermal-epidermal interface revealed primarily mononuclear cells during the first 8 h of the inflammatory response; however, their prevalence at 24 h was greatly diminished due to neutrophil infiltration. Accompanying the cellular immune response was the accumulation of inflammatory mediators in the bathing medium. The accumulation of IFN-gamma reached a plateau within 3 h; significant accumulations of the complement fragment, C5a, and of leukotriene B4 were also detected at 3 h. The accumulation of C5a did not peak until 5 h, whereas leukotriene B4 continued to accumulate through 24 h. IL-6 and IL-8 concentrations were minimal at 3-8 h but dramatic by 24 h while IL-1 beta, tumor necrosis factor-alpha, and granulocyte-macrophage colony-stimulating factor were undetectable within 3-8 h, but markedly elevated by 24 h. There was little accumulation of IL-4 and no accumulation of IL-1 alpha or IL-2 during the 24-h period. The sequential appearance of mediators at an inflammatory focus suggests that a carefully regulated dynamic system is responsible for controlling the evolution of the inflammatory response.

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Selected References

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

  1. Bazzoni F., Cassatella M. A., Rossi F., Ceska M., Dewald B., Baggiolini M. Phagocytosing neutrophils produce and release high amounts of the neutrophil-activating peptide 1/interleukin 8. J Exp Med. 1991 Mar 1;173(3):771–774. doi: 10.1084/jem.173.3.771. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Björk J., Hugli T. E., Smedegård G. Microvascular effects of anaphylatoxins C3a and C5a. J Immunol. 1985 Feb;134(2):1115–1119. [PubMed] [Google Scholar]
  3. Brandes M. E., Mai U. E., Ohura K., Wahl S. M. Type I transforming growth factor-beta receptors on neutrophils mediate chemotaxis to transforming growth factor-beta. J Immunol. 1991 Sep 1;147(5):1600–1606. [PubMed] [Google Scholar]
  4. Broudy V. C., Kaushansky K., Segal G. M., Harlan J. M., Adamson J. W. Tumor necrosis factor type alpha stimulates human endothelial cells to produce granulocyte/macrophage colony-stimulating factor. Proc Natl Acad Sci U S A. 1986 Oct;83(19):7467–7471. doi: 10.1073/pnas.83.19.7467. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Cicco N. A., Lindemann A., Content J., Vandenbussche P., Lübbert M., Gauss J., Mertelsmann R., Herrmann F. Inducible production of interleukin-6 by human polymorphonuclear neutrophils: role of granulocyte-macrophage colony-stimulating factor and tumor necrosis factor-alpha. Blood. 1990 May 15;75(10):2049–2052. [PubMed] [Google Scholar]
  6. Clancy R. M., Dahinden C. A., Hugli T. E. Arachidonate metabolism by human polymorphonuclear leukocytes stimulated by N-formyl-Met-Leu-Phe or complement component C5a is independent of phospholipase activation. Proc Natl Acad Sci U S A. 1983 Dec;80(23):7200–7204. doi: 10.1073/pnas.80.23.7200. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Dinarello C. A. Interleukin-1 and interleukin-1 antagonism. Blood. 1991 Apr 15;77(8):1627–1652. [PubMed] [Google Scholar]
  8. Djeu J. Y., Serbousek D., Blanchard D. K. Release of tumor necrosis factor by human polymorphonuclear leukocytes. Blood. 1990 Oct 1;76(7):1405–1409. [PubMed] [Google Scholar]
  9. Dubravec D. B., Spriggs D. R., Mannick J. A., Rodrick M. L. Circulating human peripheral blood granulocytes synthesize and secrete tumor necrosis factor alpha. Proc Natl Acad Sci U S A. 1990 Sep;87(17):6758–6761. doi: 10.1073/pnas.87.17.6758. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Dustin M. L., Singer K. H., Tuck D. T., Springer T. A. Adhesion of T lymphoblasts to epidermal keratinocytes is regulated by interferon gamma and is mediated by intercellular adhesion molecule 1 (ICAM-1). J Exp Med. 1988 Apr 1;167(4):1323–1340. doi: 10.1084/jem.167.4.1323. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Fava R. A., Olsen N. J., Postlethwaite A. E., Broadley K. N., Davidson J. M., Nanney L. B., Lucas C., Townes A. S. Transforming growth factor beta 1 (TGF-beta 1) induced neutrophil recruitment to synovial tissues: implications for TGF-beta-driven synovial inflammation and hyperplasia. J Exp Med. 1991 May 1;173(5):1121–1132. doi: 10.1084/jem.173.5.1121. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Follin P., Wymann M. P., Dewald B., Ceska M., Dahlgren C. Human neutrophil migration into skin chambers is associated with production of NAP-1/IL8 and C5a. Eur J Haematol. 1991 Jul;47(1):71–76. doi: 10.1111/j.1600-0609.1991.tb00564.x. [DOI] [PubMed] [Google Scholar]
  13. Grossman R. M., Krueger J., Yourish D., Granelli-Piperno A., Murphy D. P., May L. T., Kupper T. S., Sehgal P. B., Gottlieb A. B. Interleukin 6 is expressed in high levels in psoriatic skin and stimulates proliferation of cultured human keratinocytes. Proc Natl Acad Sci U S A. 1989 Aug;86(16):6367–6371. doi: 10.1073/pnas.86.16.6367. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. KAPLOW L. S. SIMPLIFIED MYELOPEROXIDASE STAIN USING BENZIDINE DIHYDROCHLORIDE. Blood. 1965 Aug;26:215–219. [PubMed] [Google Scholar]
  15. Kupper T. S. Immune and inflammatory processes in cutaneous tissues. Mechanisms and speculations. J Clin Invest. 1990 Dec;86(6):1783–1789. doi: 10.1172/JCI114907. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Larsen C. G., Anderson A. O., Appella E., Oppenheim J. J., Matsushima K. The neutrophil-activating protein (NAP-1) is also chemotactic for T lymphocytes. Science. 1989 Mar 17;243(4897):1464–1466. doi: 10.1126/science.2648569. [DOI] [PubMed] [Google Scholar]
  17. Lawrence C., Grossman R. Simple butyrate esterase stain for monocytes. Stain Technol. 1979 Nov;54(6):321–323. doi: 10.3109/10520297909110691. [DOI] [PubMed] [Google Scholar]
  18. Leonard E. J., Yoshimura T., Tanaka S., Raffeld M. Neutrophil recruitment by intradermally injected neutrophil attractant/activation protein-1. J Invest Dermatol. 1991 May;96(5):690–694. doi: 10.1111/1523-1747.ep12470612. [DOI] [PubMed] [Google Scholar]
  19. Lord P. C., Wilmoth L. M., Mizel S. B., McCall C. E. Expression of interleukin-1 alpha and beta genes by human blood polymorphonuclear leukocytes. J Clin Invest. 1991 Apr;87(4):1312–1321. doi: 10.1172/JCI115134. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Marucha P. T., Zeff R. A., Kreutzer D. L. Cytokine regulation of IL-1 beta gene expression in the human polymorphonuclear leukocyte. J Immunol. 1990 Nov 1;145(9):2932–2937. [PubMed] [Google Scholar]
  21. May L. T., Ghrayeb J., Santhanam U., Tatter S. B., Sthoeger Z., Helfgott D. C., Chiorazzi N., Grieninger G., Sehgal P. B. Synthesis and secretion of multiple forms of beta 2-interferon/B-cell differentiation factor 2/hepatocyte-stimulating factor by human fibroblasts and monocytes. J Biol Chem. 1988 Jun 5;263(16):7760–7766. [PubMed] [Google Scholar]
  22. Nickoloff B. J., Lewinsohn D. M., Butcher E. C., Krensky A. M., Clayberger C. Recombinant gamma interferon increases the binding of peripheral blood mononuclear leukocytes and a Leu-3+ T lymphocyte clone to cultured keratinocytes and to a malignant cutaneous squamous carcinoma cell line that is blocked by antibody against the LFA-1 molecule. J Invest Dermatol. 1988 Jan;90(1):17–22. doi: 10.1111/1523-1747.ep12462420. [DOI] [PubMed] [Google Scholar]
  23. Picker L. J., Michie S. A., Rott L. S., Butcher E. C. A unique phenotype of skin-associated lymphocytes in humans. Preferential expression of the HECA-452 epitope by benign and malignant T cells at cutaneous sites. Am J Pathol. 1990 May;136(5):1053–1068. [PMC free article] [PubMed] [Google Scholar]
  24. Scheja A., Forsgren A. A skin chamber technique for leukocyte migration studies; description and reproducibility. Acta Pathol Microbiol Immunol Scand C. 1985 Feb;93(1):25–30. doi: 10.1111/j.1699-0463.1985.tb02917.x. [DOI] [PubMed] [Google Scholar]
  25. Scheja A., Forsgren A. Functional properties of polymorphonuclear leukocytes accumulated in a skin chamber. Acta Pathol Microbiol Immunol Scand C. 1985 Feb;93(1):31–36. doi: 10.1111/j.1699-0463.1985.tb02918.x. [DOI] [PubMed] [Google Scholar]
  26. Sechler J. M., Malech H. L., White C. J., Gallin J. I. Recombinant human interferon-gamma reconstitutes defective phagocyte function in patients with chronic granulomatous disease of childhood. Proc Natl Acad Sci U S A. 1988 Jul;85(13):4874–4878. doi: 10.1073/pnas.85.13.4874. [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. Sehgal P. B. Interleukin-6: molecular pathophysiology. J Invest Dermatol. 1990 Jun;94(6 Suppl):2S–6S. doi: 10.1111/1523-1747.ep12874963. [DOI] [PubMed] [Google Scholar]
  28. Swensson O., Schubert C., Christophers E., Schröder J. M. Inflammatory properties of neutrophil-activating protein-1/interleukin 8 (NAP-1/IL-8) in human skin: a light- and electronmicroscopic study. J Invest Dermatol. 1991 May;96(5):682–689. doi: 10.1111/1523-1747.ep12470606. [DOI] [PubMed] [Google Scholar]
  29. Tiku K., Tiku M. L., Liu S., Skosey J. L. Normal human neutrophils are a source of a specific interleukin 1 inhibitor. J Immunol. 1986 May 15;136(10):3686–3692. [PubMed] [Google Scholar]
  30. Tiku K., Tiku M. L., Skosey J. L. Interleukin 1 production by human polymorphonuclear neutrophils. J Immunol. 1986 May 15;136(10):3677–3685. [PubMed] [Google Scholar]
  31. Wright D. G., Gallin J. I. Secretory responses of human neutrophils: exocytosis of specific (secondary) granules by human neutrophils during adherence in vitro and during exudation in vivo. J Immunol. 1979 Jul;123(1):285–294. [PubMed] [Google Scholar]
  32. Zimmerli W., Gallin J. I. Monocytes accumulate on Rebuck skin window coverslips but not in skin chamber fluid. A comparative evaluation of two in vivo migration models. J Immunol Methods. 1987 Jan 26;96(1):11–17. doi: 10.1016/0022-1759(87)90361-9. [DOI] [PubMed] [Google Scholar]
  33. Zucali J. R., Dinarello C. A., Oblon D. J., Gross M. A., Anderson L., Weiner R. S. Interleukin 1 stimulates fibroblasts to produce granulocyte-macrophage colony-stimulating activity and prostaglandin E2. J Clin Invest. 1986 Jun;77(6):1857–1863. doi: 10.1172/JCI112512. [DOI] [PMC free article] [PubMed] [Google Scholar]

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