Abstract
We describe a regulatory function of the terminal cytolytic C5b-9 complex [C5b-9(m)] of human complement. Purified C5b-9(m) complexes isolated from target membranes, whether in solution or bound to liposomes, inhibited lysis of sensitized sheep erythrocytes by whole human serum in a dose-dependent manner. C9 was not required for the inhibitory function since C5b-7 and C5b-8 complexes isolated from membranes were also effective. No effect was found with the cytolytically inactive, fluid-phase SC5b-9 complex. However, tryptic modification of SC5b-9 conferred an inhibitory capacity to the complex, due probably to partial removal of the S protein. Experiments using purified components demonstrated that C5b-9(m) exerts a regulatory effect on the formation of the classical- and alternative-pathway C3 convertases and on the utilization of C5 by cell-bound C5 convertases. C5b-9(m) complexes were unable to inhibit the lysis of cells bearing C5b-7(m) by C8 and C9. Addition of C5b-9(m) to whole human serum abolished its bactericidal effect on the serum-sensitive Escherichia coli K-12 strain W 3110 and suppressed its hemolytic function on antibody-sensitized, autologous erythrocytes. Feedback inhibition by C5b-9(m) represents a biologically relevant mechanism through which complement may autoregulate its effector functions.
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Selected References
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- Bhakdi S., Roth M. Fluid-phase SC5b-8 complex of human complement: generation and isolation from serum. J Immunol. 1981 Aug;127(2):576–580. [PubMed] [Google Scholar]
- Bhakdi S., Tranum-Jensen J. C5b-9 assembly: average binding of one C9 molecule to C5b-8 without poly-C9 formation generates a stable transmembrane pore. J Immunol. 1986 Apr 15;136(8):2999–3005. [PubMed] [Google Scholar]
- Bhakdi S., Tranum-Jensen J. Damage to mammalian cells by proteins that form transmembrane pores. Rev Physiol Biochem Pharmacol. 1987;107:147–223. doi: 10.1007/BFb0027646. [DOI] [PubMed] [Google Scholar]
- Bhakdi S., Tranum-Jensen J. Hydrophilic-amphiphilic transition of the terminal SC5b-8 complement complex through tryptic modification: biochemical and ultrastructural studies. Mol Immunol. 1982 Sep;19(9):1167–1177. doi: 10.1016/0161-5890(82)90327-3. [DOI] [PubMed] [Google Scholar]
- Bhakdi S., Tranum-Jensen J. Membrane damage by complement. Biochim Biophys Acta. 1983 Aug 11;737(3-4):343–372. doi: 10.1016/0304-4157(83)90006-0. [DOI] [PubMed] [Google Scholar]
- Bhakdi S., Tranum-Jensen J. Molecular nature of the complement lesion. Proc Natl Acad Sci U S A. 1978 Nov;75(11):5655–5659. doi: 10.1073/pnas.75.11.5655. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Bhakdi S., Tranum-Jensen J. On the cause and nature of C9-related heterogeneity of terminal complement complexes generated on target erythrocytes through the action of whole serum. J Immunol. 1984 Sep;133(3):1453–1463. [PubMed] [Google Scholar]
- Bhakdi S., Tranum-Jensen J. Terminal membrane C5b-9 complex of human complement: transition from an amphiphilic to a hydrophilic state through binding of the S protein from serum. J Cell Biol. 1982 Sep;94(3):755–759. doi: 10.1083/jcb.94.3.755. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Cole J. L., Housley G. A., Jr, Dykman T. R., MacDermott R. P., Atkinson J. P. Identification of an additional class of C3-binding membrane proteins of human peripheral blood leukocytes and cell lines. Proc Natl Acad Sci U S A. 1985 Feb;82(3):859–863. doi: 10.1073/pnas.82.3.859. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Cooper N. R., Müller-Eberhard H. J. The reaction mechanism of human C5 in immune hemolysis. J Exp Med. 1970 Oct 1;132(4):775–793. doi: 10.1084/jem.132.4.775. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Cooper N. R. The classical complement pathway: activation and regulation of the first complement component. Adv Immunol. 1985;37:151–216. doi: 10.1016/s0065-2776(08)60340-5. [DOI] [PubMed] [Google Scholar]
- Fearon D. T., Austen K. F. Properdin: binding to C3b and stabilization of the C3b-dependent C3 convertase. J Exp Med. 1975 Oct 1;142(4):856–863. doi: 10.1084/jem.142.4.856. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Fearon D. T. Regulation of the amplification C3 convertase of human complement by an inhibitory protein isolated from human erythrocyte membrane. Proc Natl Acad Sci U S A. 1979 Nov;76(11):5867–5871. doi: 10.1073/pnas.76.11.5867. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Fischer E., Kazatchkine M. D., Mecarelli-Halbwachs L. Protection of the classical and alternative complement pathway C3 convertases, stabilized by nephritic factors, from decay by the human C3b receptor. Eur J Immunol. 1984 Dec;14(12):1111–1114. doi: 10.1002/eji.1830141209. [DOI] [PubMed] [Google Scholar]
- Fischer E., Kazatchkine M. D. Surface-dependent modulation by H of C5 cleavage by the cell-bound alternative pathway C5 convertase of human complement. J Immunol. 1983 Jun;130(6):2821–2824. [PubMed] [Google Scholar]
- Giavedoni E. B., Chow Y. M., Dalmasso A. P. The functional size of the primary complement lesion in resealed erythrocyte membrane ghosts. J Immunol. 1979 Jan;122(1):240–245. [PubMed] [Google Scholar]
- Gigli I., Fujita T., Nussenzweig V. Modulation of the classical pathway C3 convertase by plasma proteins C4 binding protein and C3b inactivator. Proc Natl Acad Sci U S A. 1979 Dec;76(12):6596–6600. doi: 10.1073/pnas.76.12.6596. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Hunsicker L. G., Ruddy S., Austen K. F. Alternate complement pathway: factors involved in cobra venom factor (CoVF) activation of the third component of complement (C3). J Immunol. 1973 Jan;110(1):128–138. [PubMed] [Google Scholar]
- Hänsch G. M., Seitz M., Martinotti G., Betz M., Rauterberg E. W., Gemsa D. Macrophages release arachidonic acid, prostaglandin E2, and thromboxane in response to late complement components. J Immunol. 1984 Oct;133(4):2145–2150. [PubMed] [Google Scholar]
- Imagawa D. K., Osifchin N. E., Paznekas W. A., Shin M. L., Mayer M. M. Consequences of cell membrane attack by complement: release of arachidonate and formation of inflammatory derivatives. Proc Natl Acad Sci U S A. 1983 Nov;80(21):6647–6651. doi: 10.1073/pnas.80.21.6647. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Jenne D., Stanley K. K. Molecular cloning of S-protein, a link between complement, coagulation and cell-substrate adhesion. EMBO J. 1985 Dec 1;4(12):3153–3157. doi: 10.1002/j.1460-2075.1985.tb04058.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Kazatchkine M. D., Fearon D. T., Austen K. F. Human alternative complement pathway: membrane-associated sialic acid regulates the competition between B and beta1 H for cell-bound C3b. J Immunol. 1979 Jan;122(1):75–81. [PubMed] [Google Scholar]
- Kazatchkine M. D., Nydegger U. E. The human alternative complement pathway: biology and immunopathology of activation and regulation. Prog Allergy. 1982;30:193–234. [PubMed] [Google Scholar]
- Kroll H. P., Bhakdi S., Taylor P. W. Membrane changes induced by exposure of Escherichia coli to human serum. Infect Immun. 1983 Dec;42(3):1055–1066. doi: 10.1128/iai.42.3.1055-1066.1983. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Lachmann P. J., Thompson R. A. Reactive lysis: the complement-mediated lysis of unsensitized cells. II. The characterization of activated reactor as C56 and the participation of C8 and C9. J Exp Med. 1970 Apr 1;131(4):643–657. doi: 10.1084/jem.131.4.643. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Müller-Eberhard H. J. The membrane attack complex. Springer Semin Immunopathol. 1984;7(2-3):93–141. doi: 10.1007/BF01893017. [DOI] [PubMed] [Google Scholar]
- Nelson R. A., Jr, Jensen J., Gigli I., Tamura N. Methods for the separation, purification and measurement of nine components of hemolytic complement in guinea-pig serum. Immunochemistry. 1966 Mar;3(2):111–135. doi: 10.1016/0019-2791(66)90292-8. [DOI] [PubMed] [Google Scholar]
- Nicholson-Weller A., Burge J., Fearon D. T., Weller P. F., Austen K. F. Isolation of a human erythrocyte membrane glycoprotein with decay-accelerating activity for C3 convertases of the complement system. J Immunol. 1982 Jul;129(1):184–189. [PubMed] [Google Scholar]
- Seeger W., Suttorp N., Hellwig A., Bhakdi S. Noncytolytic terminal complement complexes may serve as calcium gates to elicit leukotriene B4 generation in human polymorphonuclear leukocytes. J Immunol. 1986 Aug 15;137(4):1286–1293. [PubMed] [Google Scholar]
- Strunk R. C., Giclas P. C. Modulation of the activity of the classical complement pathway C3 convertase by surface-bound C3 or C5. J Immunol. 1980 Feb;124(2):520–526. [PubMed] [Google Scholar]
- Tack B. D., Prahl J. W. Third component of human complement: purification from plasma and physicochemical characterization. Biochemistry. 1976 Oct 5;15(20):4513–4521. doi: 10.1021/bi00665a028. [DOI] [PubMed] [Google Scholar]