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. 1991 Mar 1;173(3):673–679. doi: 10.1084/jem.173.3.673

Tumor necrosis factor is a critical mediator in hapten induced irritant and contact hypersensitivity reactions

PMCID: PMC2118812  PMID: 1900080

Abstract

We examined the role of cytokines in the cutaneous response to the application of trinitrochlorobenzene (TNCB) in both nonsensitized and sensitized mice, i.e., in the irritant reaction (IR) and contact hypersensitivity reactions (CH). When administered immediately before challenge, anti-tumor necrosis factor (TNF) antibody abrogated the ear swelling response in CH; antibody directed against interferon gamma or antibodies to both granulocyte/macrophage colony-stimulating factor and interleukin 3 (IL-3) had a partial inhibitory effect; anti-IL-2 receptor antibody had no effect. Anti-TNF prevented the various features of the CH, as seen on histological sections, e.g., leukocyte infiltration and hemorrhages within the dermis and keratinocytes necrosis. Anti-TNF antibody also prevented the IR. The presence of TNF mRNA was evaluated on Northern blots; TNF-alpha mRNA was detectable in an untreated ear, increased after the application of TNCB in nonsensitized mice, and was highest in sensitized mice. TNF mRNA accumulation, which was evident 0.5 h after hapten application and lasted greater than 72 h, was abolished by treatment with anti-TNF antibody, thus suggesting an auto-amplification of TNF production. The cellular origin of TNF mRNA was explored by in situ hybridization; basal keratinocytes showed the highest labeling, but TNF mRNA was also detectable in cells of the dermal infiltrate. After hapten (TNCB) application at sites susceptible (the ear) or resistant (the foot pad) to CH or IR, a close correlation was observed between TNF mRNA accumulation and the intensity of the inflammatory reaction. The major role played by TNF in both the CH and the IR explains the histologically similar aspects of these reactions and the extreme variability of these reactions at various anatomical sites.

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Selected References

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  1. Avnstorp C., Ralfkiaer E., Jørgensen J., Wantzin G. L. Sequential immunophenotypic study of lymphoid infiltrate in allergic and irritant reactions. Contact Dermatitis. 1987 May;16(5):239–245. doi: 10.1111/j.1600-0536.1987.tb01445.x. [DOI] [PubMed] [Google Scholar]
  2. Beutler B., Cerami A. The biology of cachectin/TNF--a primary mediator of the host response. Annu Rev Immunol. 1989;7:625–655. doi: 10.1146/annurev.iy.07.040189.003205. [DOI] [PubMed] [Google Scholar]
  3. Bigby M., Kwan T., Sy M. S. Ratio of Langerhans cells to Thy-1+ dendritic epidermal cells in murine epidermis influences the intensity of contact hypersensitivity. J Invest Dermatol. 1987 Nov;89(5):495–499. doi: 10.1111/1523-1747.ep12460983. [DOI] [PubMed] [Google Scholar]
  4. Cher D. J., Mosmann T. R. Two types of murine helper T cell clone. II. Delayed-type hypersensitivity is mediated by TH1 clones. J Immunol. 1987 Jun 1;138(11):3688–3694. [PubMed] [Google Scholar]
  5. Collart M. A., Belin D., Vassalli J. D., Vassalli P. Modulations of functional activity in differentiated macrophages are accompanied by early and transient increase or decrease in c-fos gene transcription. J Immunol. 1987 Aug 1;139(3):949–955. [PubMed] [Google Scholar]
  6. EISEN H. N., ORRIS L., BELMAN S. Elicitation of delayed allergic skin reactions with haptens; the dependence of elicitation on hapten combination with protein. J Exp Med. 1952 May 1;95(5):473–487. doi: 10.1084/jem.95.5.473. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. FLAX M. H., CAULFIELD J. B. CELLULAR AND VASCULAR COMPONENTS OF ALLERGIC CONTACT DERMATITIS. Am J Pathol. 1963 Dec;43:1031–1053. [PMC free article] [PubMed] [Google Scholar]
  8. Fong T. A., Mosmann T. R. Alloreactive murine CD8+ T cell clones secrete the Th1 pattern of cytokines. J Immunol. 1990 Mar 1;144(5):1744–1752. [PubMed] [Google Scholar]
  9. Fong T. A., Mosmann T. R. The role of IFN-gamma in delayed-type hypersensitivity mediated by Th1 clones. J Immunol. 1989 Nov 1;143(9):2887–2893. [PubMed] [Google Scholar]
  10. Galli S. J., Hammel I. Unequivocal delayed hypersensitivity in mast cell-deficient and beige mice. Science. 1984 Nov 9;226(4675):710–713. doi: 10.1126/science.6494907. [DOI] [PubMed] [Google Scholar]
  11. Gocinski B. L., Tigelaar R. E. Roles of CD4+ and CD8+ T cells in murine contact sensitivity revealed by in vivo monoclonal antibody depletion. J Immunol. 1990 Jun 1;144(11):4121–4128. [PubMed] [Google Scholar]
  12. Grau G. E., Fajardo L. F., Piguet P. F., Allet B., Lambert P. H., Vassalli P. Tumor necrosis factor (cachectin) as an essential mediator in murine cerebral malaria. Science. 1987 Sep 4;237(4819):1210–1212. doi: 10.1126/science.3306918. [DOI] [PubMed] [Google Scholar]
  13. Grau G. E., Heremans H., Piguet P. F., Pointaire P., Lambert P. H., Billiau A., Vassalli P. Monoclonal antibody against interferon gamma can prevent experimental cerebral malaria and its associated overproduction of tumor necrosis factor. Proc Natl Acad Sci U S A. 1989 Jul;86(14):5572–5574. doi: 10.1073/pnas.86.14.5572. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Grau G. E., Kindler V., Piguet P. F., Lambert P. H., Vassalli P. Prevention of experimental cerebral malaria by anticytokine antibodies. Interleukin 3 and granulocyte macrophage colony-stimulating factor are intermediates in increased tumor necrosis factor production and macrophage accumulation. J Exp Med. 1988 Oct 1;168(4):1499–1504. doi: 10.1084/jem.168.4.1499. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Griffiths C. E., Nickoloff B. J. Keratinocyte intercellular adhesion molecule-1 (ICAM-1) expression precedes dermal T lymphocytic infiltration in allergic contact dermatitis (Rhus dermatitis). Am J Pathol. 1989 Dec;135(6):1045–1053. [PMC free article] [PubMed] [Google Scholar]
  16. Kelley V. E., Gaulton G. N., Strom T. B. Inhibitory effects of anti-interleukin 2 receptor and anti-L3T4 antibodies on delayed type hypersensitivity: the role of complement and epitope. J Immunol. 1987 May 1;138(9):2771–2775. [PubMed] [Google Scholar]
  17. Kindler V., Sappino A. P., Grau G. E., Piguet P. F., Vassalli P. The inducing role of tumor necrosis factor in the development of bactericidal granulomas during BCG infection. Cell. 1989 Mar 10;56(5):731–740. doi: 10.1016/0092-8674(89)90676-4. [DOI] [PubMed] [Google Scholar]
  18. Lowenthal J. W., Corthésy P., Tougne C., Lees R., MacDonald H. R., Nabholz M. High and low affinity IL 2 receptors: analysis by IL 2 dissociation rate and reactivity with monoclonal anti-receptor antibody PC61. J Immunol. 1985 Dec;135(6):3988–3994. [PubMed] [Google Scholar]
  19. Lynch D. H., Gurish M. F., Daynes R. A. Relationship between epidermal Langerhans cell density ATPase activity and the induction of contact hypersensitivity. J Immunol. 1981 May;126(5):1892–1897. [PubMed] [Google Scholar]
  20. Medenica M., Rostenberg A., Jr A comparative light and electron microscopic study of primary irritant contact dermatitis and allergic contact dermatitis. J Invest Dermatol. 1971 Apr;56(4):259–271. doi: 10.1111/1523-1747.ep12260992. [DOI] [PubMed] [Google Scholar]
  21. Mosmann T. R., Coffman R. L. TH1 and TH2 cells: different patterns of lymphokine secretion lead to different functional properties. Annu Rev Immunol. 1989;7:145–173. doi: 10.1146/annurev.iy.07.040189.001045. [DOI] [PubMed] [Google Scholar]
  22. Olsen W. M., Elgjo K. UVB-induced epidermal hyperproliferation is modified by a single, topical treatment with a mitosis inhibitory epidermal pentapeptide. J Invest Dermatol. 1990 Jan;94(1):101–106. doi: 10.1111/1523-1747.ep12873961. [DOI] [PubMed] [Google Scholar]
  23. Piguet P. F., Collart M. A., Grau G. E., Kapanci Y., Vassalli P. Tumor necrosis factor/cachectin plays a key role in bleomycin-induced pneumopathy and fibrosis. J Exp Med. 1989 Sep 1;170(3):655–663. doi: 10.1084/jem.170.3.655. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Piguet P. F., Collart M. A., Grau G. E., Sappino A. P., Vassalli P. Requirement of tumour necrosis factor for development of silica-induced pulmonary fibrosis. Nature. 1990 Mar 15;344(6263):245–247. doi: 10.1038/344245a0. [DOI] [PubMed] [Google Scholar]
  25. Piguet P. F., Grau G. E., Vassalli P. Subcutaneous perfusion of tumor necrosis factor induces local proliferation of fibroblasts, capillaries, and epidermal cells, or massive tissue necrosis. Am J Pathol. 1990 Jan;136(1):103–110. [PMC free article] [PubMed] [Google Scholar]
  26. Pober J. S. Warner-Lambert/Parke-Davis award lecture. Cytokine-mediated activation of vascular endothelium. Physiology and pathology. Am J Pathol. 1988 Dec;133(3):426–433. [PMC free article] [PubMed] [Google Scholar]
  27. Robinson M. K., Fletcher E. R., Johnson G. R., Wyder W. E., Maurer J. K. Value of the cutaneous basophil hypersensitivity (CBH) response for distinguishing weak contact sensitization from irritation reactions in the guinea pig. J Invest Dermatol. 1990 May;94(5):636–643. doi: 10.1111/1523-1747.ep12876210. [DOI] [PubMed] [Google Scholar]
  28. Roupe G., Ridell B. The cellular infiltrate in contact hypersensitivity to picryl chloride in the mouse. Acta Derm Venereol. 1979;59(3):191–195. [PubMed] [Google Scholar]
  29. Sappino A. P., Huarte J., Belin D., Vassalli J. D. Plasminogen activators in tissue remodeling and invasion: mRNA localization in mouse ovaries and implanting embryos. J Cell Biol. 1989 Nov;109(5):2471–2479. doi: 10.1083/jcb.109.5.2471. [DOI] [PMC free article] [PubMed] [Google Scholar]
  30. Spitalny G. L., Havell E. A. Monoclonal antibody to murine gamma interferon inhibits lymphokine-induced antiviral and macrophage tumoricidal activities. J Exp Med. 1984 May 1;159(5):1560–1565. doi: 10.1084/jem.159.5.1560. [DOI] [PMC free article] [PubMed] [Google Scholar]
  31. Spriggs D. R., Imamura K., Rodriguez C., Sariban E., Kufe D. W. Tumor necrosis factor expression in human epithelial tumor cell lines. J Clin Invest. 1988 Feb;81(2):455–460. doi: 10.1172/JCI113341. [DOI] [PMC free article] [PubMed] [Google Scholar]
  32. Taverne J., Rayner D. C., Van der Meide P. H., Lydyard P. M., Bidey S. P., Cooke A. Cytotoxicity of tumor necrosis factor for thyroid epithelial cells and its regulation by interferon-gamma. Eur J Immunol. 1987 Dec;17(12):1855–1858. doi: 10.1002/eji.1830171229. [DOI] [PubMed] [Google Scholar]

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