Abstract
Induration is a prominent feature of delayed hypersensitivity reaction (DHR), and fibrin deposition is the central mechanism. We studied the effects of two inhibitors of DHR on the activities of thrombin and plasmin in the extract of the skin site of DHR and compared the two activities in the site of DHR with those in the site of the Arthus reaction (AR) that lacks induration. Warfarin, an anticoagulant, inhibited thrombin activity and induration, but not plasmin activity. Ferritin, a blocker of a macrophage-dependent reaction, inhibited the two activities and induration. The lesion of DHR had three to four times the thrombin activity of the lesion of AR, and the activity paralleled the development of induration. In contrast, plasmin activity of the site of DHR was lower than that of the site of AR and was associated with the reduction of induration. The two protease activities in the site of AR did not correlate with the development of the AR lesion. These results suggest that thrombin and plasmin mediate the development of induration and that induration is produced by a synergistic effect of high thrombin activity and low plasmin activity in the site of DHR.
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References
Dvorak, H. F. 1974. Delayed hypersensitivity.In The Inflammatory Process, Vol III. B. W. Zweifach, L. Grant, and R. T. McCluskey, editors. Academic Press, New York. 291–345.
Colvin, R. B., M. W. Mosesson, andH. F. Dvorak. 1979. Delayed-type hypersensitivity skin reactions in congenital afibrinogenemia.J. Clin. Invest. 63:1302–1306.
Colvin, R. B., andH. F. Dvorak. 1975. Role of the clotting system in cell-mediated hypersensitivity. II. Kinetics of fibrinogen/fibrin accumulation and vascular permeability changes in tuberculin and cutaneous basophil hypersensitivity reactions.J. Immunol. 114:377–387.
Nelson, D. S. 1965. The effects of anticoagulations and other drugs on cellular and cutaneous reactions to antigen in guinea-pigs with delayed-type hypersensitivity.Immunology 9:219–234.
Edwards, R. L., andF. R. Rickles. 1978. Delayed hypersensitivity in man: Effects of systemic anticoagulation.Science 200:541–543.
Morita, T., H. Kato, S. Iwanaga, K. Takada, T. Kimura, andS. Sakakibara. 1977. New fluorogenic substrates forα-thrombin, factor Xa, kallikreins, and urokinase.J. Biochem. 82:1495–1498.
Kato, H., N. Adachi, Y. Ohno, S. Iwanaoa, K. Takada, andS. Sakakibara. 1980. New fluorogenic peptide substrates for plasmin.J. Biochem. 88:183–190.
Laura, R., D. J. Robison, andD. H. Bing. 1980. (p-Amidinophenyl)methanesulfonyl fluoride, an irreversible inhibitor of serine proteases.Biochemistry 19:4859–4864.
Imamura, T., andT. Kambara. 1991. Enzymatic investigation for delayed-type hypersensitivity reaction: Assay for thrombin and plasmin activities in tuberculin reaction sites.Acta Pathol. Jpn. 41:722–729.
Crawford, J. P., H. Z. Movat, N. S. Ranadive, andJ. B. Hay. 1982. Pathways to inflammation induced by immune complexes: Development of the Arthus reaction.Fed. Proc. 41:2583–2587.
Harada, T., M. Baba, I. Torii, andS. Morikawa. 1987. Ferritin selectively suppresses delayed-type hypersensitivity responses at induction or effector phase.Cell. Immunol. 109:75–88.
Lurie, M. B., P. Zappasodi, E. Cardona-Lynch, andA. M. Dannenberg, Jr. 1952. The response to the intracutaneous inoculation of BCG as an index of native resistance to tuberculosis.J. Immunol. 68:369–387.
Barrett, A. J., M. A. Brown, andC. A. Sayers. 1979. The electrophoretically “slow” and “fast” forms of theα 2-macroglobulin molecule.Biochem. J. 181:401–418.
Iwanaga, S., T. Morita, H. Kato, T. Harada, N. Adachi, T. Sugo, I. Maruyama, K. Takada, T. Kimura, andS. Sakakibara. 1979. Fluorogenic peptide substrates for proteases in blood coagulation, kallikrein-kinin and fibrinolysis systems.In Kinins-II, Biochemistry, Pathophysiology, and Clinical Aspects. S. Fujii, H. Moriya, and T. Suzuki, editors. Plenum Publishing, New York. 147–163.
Downing, M. R., J. W. Bloom, andK. G. Mann. 1978. Comparison of the inhibition of thrombin by three plasma protease inhibitors.Biochemistry 17:2649–2653.
Harpel, P. C. 1977. Plasmin inhibitor interactions.J. Exp. Med. 146:1033–1040.
Geczy, C. L., andP. A. Meyer. 1982. Leukocyte procoagulant activity in man: An in vitro correlate of delayed-type hypersensitivity.J. Immunol. 128:331–336.
Geczy, C. L., andK. A. Hopper. 1981. A mechanism of migration inhibition in delayed-type hypersensitivity. II. Lymphokines promote procoagulant activity of macrophages.In Vitro 126:1059–1065.
Edwards, R. L., andF. R. Rickles. 1980. The role of human T cells (and T cell products) for monocyte tissue factor generation.J. Immunol. 125:606–609.
Keown, P., andB. Descamps-Latscha. 1983. In vitro suppression of cell-mediated immunity by ferroproteins and ferric salts.Cell. Immunol. 80:257–266.
Whitlon, D. S., J. A. Sadowski, andJ. W. Suttie. 1978. Mechanism of coumarin action: Significance of vitamin K epoxide reductase inhibition.Biochemistry 17:1371–1377.
Suttie, J. W. 1985. Vitamin K-dependent carboxylase.Annu. Rev. Biochem. 54:459–477.
Dvorak, H. F., D. R. Senger, A. M. Dvorak, V. S. Harvey, andJ. McDonagh. 1985. Regulation of extravascular coagulation by microvascular permeability.Science 227:1059–1061.
Gordon, S., J. C. Unkeless, andZ. A. Cohn. 1974. Induction of macrophage plasminogen activator by endotoxin stimulation and phagocytosis: Evidence for a two-stage process.J. Exp. Med. 140:995–1010.
Gordon, S., andZ. A. Cohn. 1978. Bacille Calmette-Guerin infection in the mouse. Regulation of macrophage plasminogen activator by T lymphocytes and specific antigen.J. Exp. Med. 147:1175–1188.
Bar-Shavit, R., A. Kahn, G. D. Wilner, andJ. W. Fenton II. 1983. Monocyte chemotaxis: stimulation by specific exosite region in thrombin.Science 220:728–731.
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This work was supported in part by grants from the Japanese Ministry of Education.
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Imamura, T., Kambara, T. Role of thrombin and plasmin in development of delayed hypersensitivity reaction in guinea pig skin. Inflammation 16, 169–177 (1992). https://doi.org/10.1007/BF00918956
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DOI: https://doi.org/10.1007/BF00918956