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Effects of serine protease inhibitor, tame, on IL-1β in LPS-stimulated human monocytes: Relationship between synthesis and release of a 33-kDa precursor and the 17-kDa biologically active species

Abstract

LPS stimulation of human monocytes in vitro induced release of the 17-kDa mature IL-1β (mIL-1β) but did not result in release of precursor IL-1β (pIL-1β). In contrast, the presence of a serine protease inhibitor, Nα-(p-toluene sulfonyl)-L-arginine methyl ester (TAME; 10 mM) for 6 or 18 h was associated with the LPS-stimulated release of the 33-kDa pIL-1β as well. These effects were initially discerned from observations that the fraction of the total IL-1β produced (as detected by ELISA) that was released from monocytes increased in the presence of TAME, and immunoblot assays confirmed that this fraction was predominantly 33-kDa IL-1β. A global decrease in monocyte protein synthesis was also observed after prolonged (18-h) exposure to TAME and was associated with a decrease in IL-1β synthesis, predominantly affecting 31-kDa pIL-1β, and a dose-dependent inhibition of TNF-α production. Parallel examination of lactate dehydrogenase (LDH) release indicated thatpIL-1β release was unrelated to cell lysis. These results demonstrate that TAME-inhibitable serine proteases are probably involved in the production and eventual proteolysis of the 33-kDa pIL-1β in situ but are probably not mechanistically related to either maturation of the IL-1β molecule or signaling of IL-1β release. IL-1β release appears to be dependent on the amount of total IL-1β synthesized. Serine proteolysis may constitute a degradative pathway for excess precursor, which, if interfered with, could result in release of the higher-molecular-weight forms of IL-1β.

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References

  1. 1.

    March, C. J., B. Mosley, A. Larsen, D. P. Cerretti, G. Braedt, V. Price, S. Gillis, C. S. Henney, S. R. Kronhein, K. Grabstein, P. J. Conlon, T. P. Hopps, andD. Cosman. 1985. Cloning, sequence and expression of two distinct human interleukin-1 complementary DNA's.Nature 315:641–647.

  2. 2.

    Clark, B. C., K. L. Collins, M. S. Gandy, A. C. Webb, andP. E. Auton. 1986. Genomic sequence for human prointerleukin 1 beta: Possible evolution from a reverse transcribed prointerleukin 1 alpha gene.Nucleic Acids Res. 14:7897–7899.

  3. 3.

    Hazuda, D. J., J. C. Lee, andP. R. Young. 1988. Kinetics of interleukin-1 secretion from activated monocytes: Differences between interleukin-1α and interleukin-1β.J. Biol. Chem. 263:8473–8479.

  4. 4.

    Lonneman, G., S. Endres, J. W. Van der Meer, J. G. Cannon, K. M. Kock, andC. A. Dinarello. 1989. Differences in the synthesis and kinetics of release of interleukin-la, interleukin-1β and tumor necrosis factor from human mononuclear cells.Eur. J. Immunol. 19:1531–1536.

  5. 5.

    Rubartelli, A., F. Cozzolino, M. Talio, andR. Sitia. 1990. A novel secretory pathway for interleukin-1β, a protein lacking a signal sequence.EMBO J. 9:1503–1510.

  6. 6.

    Giri, J. G., P. T. Lomedico, andS. B. Mizel. 1985. Studies on the synthesis and secretion of interleukin-1. I. A 33,000 molecular weight precursor for interleukin-1.J. Immunol. 134:343–349.

  7. 7.

    Limjuco, G., S. Galuska, J. Chin, P. Cameron, J. Boger, andJ. A. Schmidt. 1986. Antibodies of predetermined specificity to the major charged species of human interleukin-1.Proc. Nad. Acad. Sci. U.S.A. 83:3973–3976.

  8. 8.

    Thornberry, N., H. Bull, J. Calaycay, K. Chapman, A. Howard, M. Kostura, D. Miller, S. Molineau, J. Weidner, J. Aunins, K. Elliston, J. Ayala, F. Casanol, J. Chin, G. Ding, L. Egger, E. Gaffney, G. Limjuco, O. Palyha, S. Raju, A. Rolando, J. Salley, T. Yamin, T. Lee, J. Shively, M. Maccross, R. Mumford, J. Schmidt, andM. Tocci. 1992. A novel heterodimeric cysteine protease is required for interleukin-1β processing in monocytes.Nature 356:768–774.

  9. 9.

    Hannun, C. H., C. J. Wilcox, W. P. Arend, andF. G. Joslin. 1990. Interleukin-1 receptor antagonist activity of a human interleukin-1 inhibitor.Nature 343:336–340.

  10. 10.

    Eisenberg, S. P., K. J. Evans, W. P. Arend, andE. Verderber. 1990. Primary structure and functional expression from complementary DNA of a human interleukin-1 receptor antagonist.Nature 343:341–346.

  11. 11.

    Wakabayashi, G. 1991. A specific receptor antagonist for interleukin-1 prevents Escherichia coli-induced shock in rabbits.FASEB J. 5:338–343.

  12. 12.

    Fanslow, W. 1990. Regulation of alloreactivity in vivo by a soluble form of the interleukin-1 receptor.Science 248:739–742.

  13. 13.

    McIntyre, K., G. J. Stepan, K. D. Kolinsky, andW. R. Benjamin. 1991. Inhibition of interleukin-1 (IL-1) binding and bioactivity in vitro and modulation of acute inflammation in vivo by IL-1 receptor antagonist and anti-IL-1 receptor monoclonal antibody.J. Exp. Med. 173:931–939.

  14. 14.

    Cerretti, P., C. Kozlosky, B. Mosley, N. Nelson, K. Van Ness, T. Greenstreet, C. March, S. Kronheim, T. Druck, L. Cannizzaro, K. Huebner, andR. Black. 1992. Molecular cloning of the interleukin-1β converting enzyme.Science 256:97–100.

  15. 15.

    Hazuda, D., J. Strickler, F. Keuppers, P. Simon, andP. Young. 1990. Processing of precursor interleukin 1β and inflammatory disease.J. Biol. Chem. 265:6318–6322.

  16. 16.

    Matsuchima, K., M. Taguchi, E. Kovacs, H. Yoiung, andJ. Oppenheim. 1986. Intracellular localization of human monocyte associated interleukin 1 (IL 1) activity and release of biologically active IL 1 from monocytes by trypsin and plasmin.J. Immunol. 136:2883–2891.

  17. 17.

    Yam, J. T., C. Y. Li, andW. H. Crosby. 1971. Cytochemical identification of monocytes and granulocytes.Am. J. Clin. Pathol. 55:283–287.

  18. 18.

    Abrahamsen, T. G., C. S. Carter, E. J. Read, M. Rubin, H. G. Goetzman, E. F. Lizzio, Y. L. Lee, M. Hansen, P. A. Pizzo, andT. Huffman. 1991. Stimulatory effect of counterflow centrifugal elutriation in large-scale separation of peripheral blood monocytes can be reversed by storing the cells at 37 degrees C.J. Clin. Apher. 6:48–53.

  19. 19.

    Decker, T., andM. Lohmann-Matthes. 1988. A quick and simple method for the quantitation of lactate dehydrogenase release in measurements of cellular cytotoxicity and tumor necrosis factor (TNF) activity.J. Immunol. Methods 15:61–69.

  20. 20.

    Hochstein, D. H. 1988. U.S. government quality control program for limulus amebocyte lysate and endotoxin.In Bacterial Endotoxins: Structure, Biomedical Significance, and Detection with theLimulus Amebocyte Lysate Test. Alan R. Liss, New York. 221–239.

  21. 21.

    Jessop, J., andT. Hoffman. 1992. Production and release of IL-1β by human peripheral blood monocytes in response to diverse stimuli: Possible role of “microdamage” to account for unregulated release.Lymphokine Cytokine Res. 12(1):51–58.

  22. 22.

    Endres, S., H. J. Fulle, B. Sinha, D. Stoll, C. A. Dinarello, R. Gerzer, andP. Weber. 1991. Cyclic nucleotides differentially regulate the synthesis of tumour necrosis factor-α by human mononuclear cells.Immunology 72:56–60.

  23. 23.

    Sampaio, E., E. Sarno, R. Galilly, Z. Cohn, andG. Kaplan. 1991. Thalidomide selectively inhibits tumor necrosis factorα production by stimulated human monocytes.J. Exp. Med. 173:699–703.

  24. 24.

    Scuderi, P. 1989. Suppression of human leukocyte tumor necrosis factor secretion by the serine protease inhibitor p-toluenesulfonyl-L-arginine methyl ester (TAME).J. Immunol. 143:168–173.

  25. 25.

    Arend, W. P., D. F. Gordon, W. M. Wood, R. W. Janson, F. G. Joslin, andS. Jameel. 1989. IL-1β production in cultured human monocytes is regulated at multiple levels.J. Immunol. 143:118–126.

  26. 26.

    Hogquist, K. A., E. R. Unanue, andD. Chaplin. 1991. Release of IL-1 from mononuclear phagocytes.J. Immunol. 147:181–2186.

  27. 27.

    Van de Winkel, J., M. Jansze, andP. Capel. 1990. Effect of protease inhibitors on human monocyte IgG Fc receptor II. Evidence that serine esterase activity is essential for FcγRII-mediated binding.J. Immunol. 145:1890–1896.

  28. 28.

    Ruggiero, M., andE. G. Lapetina. 1986. Protease and cyclooxygenase inhibitors synergistically prevent activation of human platelets.Proc. Natl. Acad. Sci. U.S.A. 83:3456–3459.

  29. 29.

    Debets, J., J. Van de Winkel, J. Ceuppens, I. Dieteren, andW. Buurman. 1990. Crosslinking of both FcγRI and FCγRII induces secretion of tumor necrosis factor by human monocytes, requiring high affinity Fc-FcγR interactions: Functional activation of FcγRII by treatment with proteases or neuraminidase.J. Immunol. 144:1304–1310.

  30. 30.

    Smith, M., F. Kueppers, andJ. Lee. 1991. Differential regulation of interleukin-1α and interleukin-1β mRNA expression in human monocytes: Evidence for protein kinase C-dependent and -independent pathways.Lymphokine Cytokine Res. 10:397–403.

  31. 31.

    Taniguchi, H., T. Sakano, T. Hamasaki, H. Kashiwa, andK. Ueda. 1989. Effect of protein kinase C inhibitor (H7) and calmodulin antagonist (W7) on pertussis toxin-induced IL-1 production by human adherent monocytes. Comparison with lipopolysaccharide as a stimulator of IL-1 production.Immunology 67:210–215.

  32. 32.

    Barouche, O., J. Moreau, andL. Lachman. 1992. Secretion of IL-1: Role of protein kinase C.J. Immunol. 148:84–91.

  33. 33.

    Tamura, S., C. Schwartz, J. Whipple, R. Dubler, Y. Fujita-Yamaguchi, andJ. Larner. 1984. Selective inhibition of the insulin-stimulated phosphorylation of the 95,000 dalton subunit of the insulin receptor by TAME or BAEE.Kochern. Biophys. Res. Commun. 119:465–469.

  34. 34.

    Kobayashi, Y., J. Oppenheim, andK. Matsushima. 1991. Human pre-interleukin 1α andβ: Structural features revealed by limited proteolysis.Chem. Pharm. Bull. 39:1513–1517.

  35. 35.

    Dinarello, C., andN. Savage. 1989. Interleukin-1 and its receptor.Crit. Rev. Immunol. 9:1–20.

  36. 36.

    McMahan, C., J. Slack, B. Mosley, D. Cosman, S. Lupton, L. Brunton, C. Grubin, J. Wignall, N. Jenkins, C. Brannan, N. Copeland, K. Huebner, C. Croce, L. Cannizarro, D. Benjamin, S. Dower, M. Spriggs, andJ. Sims. 1991. A novel IL-1 receptor, cloned from B cells by mammalian expression, is expressed in many cell types.EMBO J. 10:2821–2832.

  37. 37.

    Hovi, T., D. Mosher, andA. Vaheri. 1977. Cultured human monocytes synthesize and secrete α2-macroglobulin.J. Exp. Med. 145:1580–1589.

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Jessop, J.J., Henry, S.L. & Hoffman, T. Effects of serine protease inhibitor, tame, on IL-1β in LPS-stimulated human monocytes: Relationship between synthesis and release of a 33-kDa precursor and the 17-kDa biologically active species. Inflammation 17, 613–631 (1993). https://doi.org/10.1007/BF00914198

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Keywords

  • Human Monocyte
  • Tame
  • Sulfonyl
  • Serine Protease Inhibitor
  • Degradative Pathway