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. 1995 Jan;95(1):89–103. doi: 10.1172/JCI117680

Interleukin-8 gene induction in the myocardium after ischemia and reperfusion in vivo.

G L Kukielka 1, C W Smith 1, G J LaRosa 1, A M Manning 1, L H Mendoza 1, T J Daly 1, B J Hughes 1, K A Youker 1, H K Hawkins 1, L H Michael 1, et al.
PMCID: PMC295378  PMID: 7814650

Abstract

Neutrophil adhesion and direct cytotoxicity for cardiac myocytes require chemotactic stimulation and are dependent upon CD18-ICAM-1 binding. To characterize the potential role of IL-8 in this interaction, canine IL-8 cDNA was cloned and the mature recombinant protein expressed in Escherichia coli BL21 cells. Recombinant canine IL-8 markedly increased adhesion of neutrophils to isolated canine cardiac myocytes. This adhesion resulted in direct cytotoxicity for cardiac myocytes. Both processes were specifically blocked by antibodies directed against CD18 and IL-8. In vivo, after 1 h of coronary occlusion, IL-8 mRNA was markedly and consistently induced in reperfused segments of myocardium. IL-8 mRNA was not induced in control (normally perfused) myocardial segments. Minimal amounts of IL-8 mRNA were detected after 3 or 4 h of ischemia without reperfusion. Highest levels of induction were evident in the most ischemic myocardial segments. IL-8 mRNA peaked in the first 3 h of reperfusion and persisted at high levels beyond 24 h. IL-8 staining was present in the inflammatory infiltrate near the border between necrotic and viable myocardium, as well as in small veins in the same area. These findings provide the first direct evidence for regulation of IL-8 in ischemic and reperfused canine myocardium and support the hypothesis that IL-8 participates in neutrophil-mediated myocardial injury.

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Selected References

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

  1. Baggiolini M., Walz A., Kunkel S. L. Neutrophil-activating peptide-1/interleukin 8, a novel cytokine that activates neutrophils. J Clin Invest. 1989 Oct;84(4):1045–1049. doi: 10.1172/JCI114265. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Beutler B., Thompson P., Keyes J., Hagerty K., Crawford D. Assay of a ribonuclease that preferentially hydrolyses mRNAs containing cytokine-derived UA-rich instability sequences. Biochem Biophys Res Commun. 1988 May 16;152(3):973–980. doi: 10.1016/s0006-291x(88)80379-6. [DOI] [PubMed] [Google Scholar]
  3. Birnstiel M. L., Busslinger M., Strub K. Transcription termination and 3' processing: the end is in site! Cell. 1985 Jun;41(2):349–359. doi: 10.1016/s0092-8674(85)80007-6. [DOI] [PubMed] [Google Scholar]
  4. Caput D., Beutler B., Hartog K., Thayer R., Brown-Shimer S., Cerami A. Identification of a common nucleotide sequence in the 3'-untranslated region of mRNA molecules specifying inflammatory mediators. Proc Natl Acad Sci U S A. 1986 Mar;83(6):1670–1674. doi: 10.1073/pnas.83.6.1670. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Carlos T., Kovach N., Schwartz B., Rosa M., Newman B., Wayner E., Benjamin C., Osborn L., Lobb R., Harlan J. Human monocytes bind to two cytokine-induced adhesive ligands on cultured human endothelial cells: endothelial-leukocyte adhesion molecule-1 and vascular cell adhesion molecule-1. Blood. 1991 May 15;77(10):2266–2271. [PubMed] [Google Scholar]
  6. Chomczynski P., Sacchi N. Single-step method of RNA isolation by acid guanidinium thiocyanate-phenol-chloroform extraction. Anal Biochem. 1987 Apr;162(1):156–159. doi: 10.1006/abio.1987.9999. [DOI] [PubMed] [Google Scholar]
  7. Clemens M. J. A potential role for RNA transcribed from B2 repeats in the regulation of mRNA stability. Cell. 1987 Apr 24;49(2):157–158. doi: 10.1016/0092-8674(87)90553-8. [DOI] [PubMed] [Google Scholar]
  8. Crawford M. H., Grover F. L., Kolb W. P., McMahan C. A., O'Rourke R. A., McManus L. M., Pinckard R. N. Complement and neutrophil activation in the pathogenesis of ischemic myocardial injury. Circulation. 1988 Dec;78(6):1449–1458. doi: 10.1161/01.cir.78.6.1449. [DOI] [PubMed] [Google Scholar]
  9. Detmers P. A., Lo S. K., Olsen-Egbert E., Walz A., Baggiolini M., Cohn Z. A. Neutrophil-activating protein 1/interleukin 8 stimulates the binding activity of the leukocyte adhesion receptor CD11b/CD18 on human neutrophils. J Exp Med. 1990 Apr 1;171(4):1155–1162. doi: 10.1084/jem.171.4.1155. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Dreyer W. J., Michael L. H., Nguyen T., Smith C. W., Anderson D. C., Entman M. L., Rossen R. D. Kinetics of C5a release in cardiac lymph of dogs experiencing coronary artery ischemia-reperfusion injury. Circ Res. 1992 Dec;71(6):1518–1524. doi: 10.1161/01.res.71.6.1518. [DOI] [PubMed] [Google Scholar]
  11. Dreyer W. J., Michael L. H., West M. S., Smith C. W., Rothlein R., Rossen R. D., Anderson D. C., Entman M. L. Neutrophil accumulation in ischemic canine myocardium. Insights into time course, distribution, and mechanism of localization during early reperfusion. Circulation. 1991 Jul;84(1):400–411. doi: 10.1161/01.cir.84.1.400. [DOI] [PubMed] [Google Scholar]
  12. Dreyer W. J., Smith C. W., Michael L. H., Rossen R. D., Hughes B. J., Entman M. L., Anderson D. C. Canine neutrophil activation by cardiac lymph obtained during reperfusion of ischemic myocardium. Circ Res. 1989 Dec;65(6):1751–1762. doi: 10.1161/01.res.65.6.1751. [DOI] [PubMed] [Google Scholar]
  13. Ember J. A., Sanderson S. D., Hugli T. E., Morgan E. L. Induction of interleukin-8 synthesis from monocytes by human C5a anaphylatoxin. Am J Pathol. 1994 Feb;144(2):393–403. [PMC free article] [PubMed] [Google Scholar]
  14. Entman M. L., Youker K., Shappell S. B., Siegel C., Rothlein R., Dreyer W. J., Schmalstieg F. C., Smith C. W. Neutrophil adherence to isolated adult canine myocytes. Evidence for a CD18-dependent mechanism. J Clin Invest. 1990 May;85(5):1497–1506. doi: 10.1172/JCI114596. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Entman M. L., Youker K., Shoji T., Kukielka G., Shappell S. B., Taylor A. A., Smith C. W. Neutrophil induced oxidative injury of cardiac myocytes. A compartmented system requiring CD11b/CD18-ICAM-1 adherence. J Clin Invest. 1992 Oct;90(4):1335–1345. doi: 10.1172/JCI115999. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Furie M. B., Tancinco M. C., Smith C. W. Monoclonal antibodies to leukocyte integrins CD11a/CD18 and CD11b/CD18 or intercellular adhesion molecule-1 inhibit chemoattractant-stimulated neutrophil transendothelial migration in vitro. Blood. 1991 Oct 15;78(8):2089–2097. [PubMed] [Google Scholar]
  17. Goddard-Finegold J., Michael L. H. Cerebral blood flow and experimental intraventricular hemorrhage. Pediatr Res. 1984 Jan;18(1):7–11. [PubMed] [Google Scholar]
  18. Goodman R. B., Foster D. C., Mathewes S. L., Osborn S. G., Kuijper J. L., Forstrom J. W., Martin T. R. Molecular cloning of porcine alveolar macrophage-derived neutrophil chemotactic factors I and II; identification of porcine IL-8 and another intercrine-alpha protein. Biochemistry. 1992 Nov 3;31(43):10483–10490. doi: 10.1021/bi00158a011. [DOI] [PubMed] [Google Scholar]
  19. Gusella G. L., Musso T., Bosco M. C., Espinoza-Delgado I., Matsushima K., Varesio L. IL-2 up-regulates but IFN-gamma suppresses IL-8 expression in human monocytes. J Immunol. 1993 Sep 1;151(5):2725–2732. [PubMed] [Google Scholar]
  20. Hechtman D. H., Cybulsky M. I., Fuchs H. J., Baker J. B., Gimbrone M. A., Jr Intravascular IL-8. Inhibitor of polymorphonuclear leukocyte accumulation at sites of acute inflammation. J Immunol. 1991 Aug 1;147(3):883–892. [PubMed] [Google Scholar]
  21. Heymann M. A., Payne B. D., Hoffman J. I., Rudolph A. M. Blood flow measurements with radionuclide-labeled particles. Prog Cardiovasc Dis. 1977 Jul-Aug;20(1):55–79. doi: 10.1016/s0033-0620(77)80005-4. [DOI] [PubMed] [Google Scholar]
  22. Hill J. H., Ward P. A. The phlogistic role of C3 leukotactic fragments in myocardial infarcts of rats. J Exp Med. 1971 Apr 1;133(4):885–900. doi: 10.1084/jem.133.4.885. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Hébert C. A., Luscinskas F. W., Kiely J. M., Luis E. A., Darbonne W. C., Bennett G. L., Liu C. C., Obin M. S., Gimbrone M. A., Jr, Baker J. B. Endothelial and leukocyte forms of IL-8. Conversion by thrombin and interactions with neutrophils. J Immunol. 1990 Nov 1;145(9):3033–3040. [PubMed] [Google Scholar]
  24. Karakurum M., Shreeniwas R., Chen J., Pinsky D., Yan S. D., Anderson M., Sunouchi K., Major J., Hamilton T., Kuwabara K. Hypoxic induction of interleukin-8 gene expression in human endothelial cells. J Clin Invest. 1994 Apr;93(4):1564–1570. doi: 10.1172/JCI117135. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Kowalski J., Denhardt D. T. Regulation of the mRNA for monocyte-derived neutrophil-activating peptide in differentiating HL60 promyelocytes. Mol Cell Biol. 1989 May;9(5):1946–1957. doi: 10.1128/mcb.9.5.1946. [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. Kozak M. An analysis of 5'-noncoding sequences from 699 vertebrate messenger RNAs. Nucleic Acids Res. 1987 Oct 26;15(20):8125–8148. doi: 10.1093/nar/15.20.8125. [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. Kozak M. Point mutations define a sequence flanking the AUG initiator codon that modulates translation by eukaryotic ribosomes. Cell. 1986 Jan 31;44(2):283–292. doi: 10.1016/0092-8674(86)90762-2. [DOI] [PubMed] [Google Scholar]
  28. Kuijpers T. W., Hakkert B. C., Hart M. H., Roos D. Neutrophil migration across monolayers of cytokine-prestimulated endothelial cells: a role for platelet-activating factor and IL-8. J Cell Biol. 1992 May;117(3):565–572. doi: 10.1083/jcb.117.3.565. [DOI] [PMC free article] [PubMed] [Google Scholar]
  29. Kukielka G. L., Hawkins H. K., Michael L., Manning A. M., Youker K., Lane C., Entman M. L., Smith C. W., Anderson D. C. Regulation of intercellular adhesion molecule-1 (ICAM-1) in ischemic and reperfused canine myocardium. J Clin Invest. 1993 Sep;92(3):1504–1516. doi: 10.1172/JCI116729. [DOI] [PMC free article] [PubMed] [Google Scholar]
  30. Laudanna C., Constantin G., Baron P., Scarpini E., Scarlato G., Cabrini G., Dechecchi C., Rossi F., Cassatella M. A., Berton G. Sulfatides trigger increase of cytosolic free calcium and enhanced expression of tumor necrosis factor-alpha and interleukin-8 mRNA in human neutrophils. Evidence for a role of L-selectin as a signaling molecule. J Biol Chem. 1994 Feb 11;269(6):4021–4026. [PubMed] [Google Scholar]
  31. Lefer D. J., Shandelya S. M., Serrano C. V., Jr, Becker L. C., Kuppusamy P., Zweier J. L. Cardioprotective actions of a monoclonal antibody against CD-18 in myocardial ischemia-reperfusion injury. Circulation. 1993 Oct;88(4 Pt 1):1779–1787. doi: 10.1161/01.cir.88.4.1779. [DOI] [PubMed] [Google Scholar]
  32. Lindley I., Aschauer H., Seifert J. M., Lam C., Brunowsky W., Kownatzki E., Thelen M., Peveri P., Dewald B., von Tscharner V. Synthesis and expression in Escherichia coli of the gene encoding monocyte-derived neutrophil-activating factor: biological equivalence between natural and recombinant neutrophil-activating factor. Proc Natl Acad Sci U S A. 1988 Dec;85(23):9199–9203. doi: 10.1073/pnas.85.23.9199. [DOI] [PMC free article] [PubMed] [Google Scholar]
  33. Ma X. L., Tsao P. S., Lefer A. M. Antibody to CD-18 exerts endothelial and cardiac protective effects in myocardial ischemia and reperfusion. J Clin Invest. 1991 Oct;88(4):1237–1243. doi: 10.1172/JCI115427. [DOI] [PMC free article] [PubMed] [Google Scholar]
  34. Ma X. L., Weyrich A. S., Lefer D. J., Buerke M., Albertine K. H., Kishimoto T. K., Lefer A. M. Monoclonal antibody to L-selectin attenuates neutrophil accumulation and protects ischemic reperfused cat myocardium. Circulation. 1993 Aug;88(2):649–658. doi: 10.1161/01.cir.88.2.649. [DOI] [PubMed] [Google Scholar]
  35. Matsushima K., Morishita K., Yoshimura T., Lavu S., Kobayashi Y., Lew W., Appella E., Kung H. F., Leonard E. J., Oppenheim J. J. Molecular cloning of a human monocyte-derived neutrophil chemotactic factor (MDNCF) and the induction of MDNCF mRNA by interleukin 1 and tumor necrosis factor. J Exp Med. 1988 Jun 1;167(6):1883–1893. doi: 10.1084/jem.167.6.1883. [DOI] [PMC free article] [PubMed] [Google Scholar]
  36. Miller M. D., Krangel M. S. Biology and biochemistry of the chemokines: a family of chemotactic and inflammatory cytokines. Crit Rev Immunol. 1992;12(1-2):17–46. [PubMed] [Google Scholar]
  37. Müller W. E., Slor H., Pfeifer K., Hühn P., Bek A., Orsulic S., Ushijima H., Schröder H. C. Association of AUUUA-binding protein with A+U-rich mRNA during nucleo-cytoplasmic transport. J Mol Biol. 1992 Aug 5;226(3):721–733. doi: 10.1016/0022-2836(92)90628-w. [DOI] [PubMed] [Google Scholar]
  38. Pinckard R. N., Olson M. S., Giclas P. C., Terry R., Boyer J. T., O'Rourke R. A. Consumption of classical complement components by heart subcellular membranes in vitro and in patients after acute myocardial infarction. J Clin Invest. 1975 Sep;56(3):740–750. doi: 10.1172/JCI108145. [DOI] [PMC free article] [PubMed] [Google Scholar]
  39. Rossen R. D., Michael L. H., Kagiyama A., Savage H. E., Hanson G., Reisberg M. A., Moake J. N., Kim S. H., Self D., Weakley S. Mechanism of complement activation after coronary artery occlusion: evidence that myocardial ischemia in dogs causes release of constituents of myocardial subcellular origin that complex with human C1q in vivo. Circ Res. 1988 Mar;62(3):572–584. doi: 10.1161/01.res.62.3.572. [DOI] [PubMed] [Google Scholar]
  40. Rossen R. D., Swain J. L., Michael L. H., Weakley S., Giannini E., Entman M. L. Selective accumulation of the first component of complement and leukocytes in ischemic canine heart muscle. A possible initiator of an extra myocardial mechanism of ischemic injury. Circ Res. 1985 Jul;57(1):119–130. doi: 10.1161/01.res.57.1.119. [DOI] [PubMed] [Google Scholar]
  41. Rot A. Binding of neutrophil attractant/activation protein-1 (interleukin 8) to resident dermal cells. Cytokine. 1992 Sep;4(5):347–352. doi: 10.1016/1043-4666(92)90077-5. [DOI] [PubMed] [Google Scholar]
  42. Rot A. Chemotactic potency of recombinant human neutrophil attractant/activation protein-1 (interleukin-8) for polymorphonuclear leukocytes of different species. Cytokine. 1991 Jan;3(1):21–27. doi: 10.1016/1043-4666(91)90006-y. [DOI] [PubMed] [Google Scholar]
  43. Rot A. Neutrophil attractant/activation protein-1 (interleukin-8) induces in vitro neutrophil migration by haptotactic mechanism. Eur J Immunol. 1993 Jan;23(1):303–306. doi: 10.1002/eji.1830230150. [DOI] [PubMed] [Google Scholar]
  44. Sanger F., Nicklen S., Coulson A. R. DNA sequencing with chain-terminating inhibitors. Proc Natl Acad Sci U S A. 1977 Dec;74(12):5463–5467. doi: 10.1073/pnas.74.12.5463. [DOI] [PMC free article] [PubMed] [Google Scholar]
  45. Schägger H., von Jagow G. Tricine-sodium dodecyl sulfate-polyacrylamide gel electrophoresis for the separation of proteins in the range from 1 to 100 kDa. Anal Biochem. 1987 Nov 1;166(2):368–379. doi: 10.1016/0003-2697(87)90587-2. [DOI] [PubMed] [Google Scholar]
  46. Sekido N., Mukaida N., Harada A., Nakanishi I., Watanabe Y., Matsushima K. Prevention of lung reperfusion injury in rabbits by a monoclonal antibody against interleukin-8. Nature. 1993 Oct 14;365(6447):654–657. doi: 10.1038/365654a0. [DOI] [PubMed] [Google Scholar]
  47. Shandelya S. M., Kuppusamy P., Herskowitz A., Weisfeldt M. L., Zweier J. L. Soluble complement receptor type 1 inhibits the complement pathway and prevents contractile failure in the postischemic heart. Evidence that complement activation is required for neutrophil-mediated reperfusion injury. Circulation. 1993 Dec;88(6):2812–2826. doi: 10.1161/01.cir.88.6.2812. [DOI] [PubMed] [Google Scholar]
  48. Shappell S. B., Toman C., Anderson D. C., Taylor A. A., Entman M. L., Smith C. W. Mac-1 (CD11b/CD18) mediates adherence-dependent hydrogen peroxide production by human and canine neutrophils. J Immunol. 1990 Apr 1;144(7):2702–2711. [PubMed] [Google Scholar]
  49. Shaw G., Kamen R. A conserved AU sequence from the 3' untranslated region of GM-CSF mRNA mediates selective mRNA degradation. Cell. 1986 Aug 29;46(5):659–667. doi: 10.1016/0092-8674(86)90341-7. [DOI] [PubMed] [Google Scholar]
  50. Simpson P. J., Todd R. F., 3rd, Fantone J. C., Mickelson J. K., Griffin J. D., Lucchesi B. R. Reduction of experimental canine myocardial reperfusion injury by a monoclonal antibody (anti-Mo1, anti-CD11b) that inhibits leukocyte adhesion. J Clin Invest. 1988 Feb;81(2):624–629. doi: 10.1172/JCI113364. [DOI] [PMC free article] [PubMed] [Google Scholar]
  51. Simpson P. J., Todd R. F., 3rd, Mickelson J. K., Fantone J. C., Gallagher K. P., Lee K. A., Tamura Y., Cronin M., Lucchesi B. R. Sustained limitation of myocardial reperfusion injury by a monoclonal antibody that alters leukocyte function. Circulation. 1990 Jan;81(1):226–237. doi: 10.1161/01.cir.81.1.226. [DOI] [PubMed] [Google Scholar]
  52. Smith C. W., Entman M. L., Lane C. L., Beaudet A. L., Ty T. I., Youker K., Hawkins H. K., Anderson D. C. Adherence of neutrophils to canine cardiac myocytes in vitro is dependent on intercellular adhesion molecule-1. J Clin Invest. 1991 Oct;88(4):1216–1223. doi: 10.1172/JCI115424. [DOI] [PMC free article] [PubMed] [Google Scholar]
  53. Smith C. W., Hollers J. C., Patrick R. A., Hassett C. Motility and adhesiveness in human neutrophils. Effects of chemotactic factors. J Clin Invest. 1979 Feb;63(2):221–229. doi: 10.1172/JCI109293. [DOI] [PMC free article] [PubMed] [Google Scholar]
  54. Smith C. W., Marlin S. D., Rothlein R., Toman C., Anderson D. C. Cooperative interactions of LFA-1 and Mac-1 with intercellular adhesion molecule-1 in facilitating adherence and transendothelial migration of human neutrophils in vitro. J Clin Invest. 1989 Jun;83(6):2008–2017. doi: 10.1172/JCI114111. [DOI] [PMC free article] [PubMed] [Google Scholar]
  55. Smith C. W., Rothlein R., Hughes B. J., Mariscalco M. M., Rudloff H. E., Schmalstieg F. C., Anderson D. C. Recognition of an endothelial determinant for CD 18-dependent human neutrophil adherence and transendothelial migration. J Clin Invest. 1988 Nov;82(5):1746–1756. doi: 10.1172/JCI113788. [DOI] [PMC free article] [PubMed] [Google Scholar]
  56. Springer T. A. Traffic signals for lymphocyte recirculation and leukocyte emigration: the multistep paradigm. Cell. 1994 Jan 28;76(2):301–314. doi: 10.1016/0092-8674(94)90337-9. [DOI] [PubMed] [Google Scholar]
  57. Strieter R. M., Kasahara K., Allen R. M., Standiford T. J., Rolfe M. W., Becker F. S., Chensue S. W., Kunkel S. L. Cytokine-induced neutrophil-derived interleukin-8. Am J Pathol. 1992 Aug;141(2):397–407. [PMC free article] [PubMed] [Google Scholar]
  58. Strieter R. M., Kunkel S. L., Showell H. J., Marks R. M. Monokine-induced gene expression of a human endothelial cell-derived neutrophil chemotactic factor. Biochem Biophys Res Commun. 1988 Nov 15;156(3):1340–1345. doi: 10.1016/s0006-291x(88)80779-4. [DOI] [PubMed] [Google Scholar]
  59. Strieter R. M., Kunkel S. L., Showell H. J., Remick D. G., Phan S. H., Ward P. A., Marks R. M. Endothelial cell gene expression of a neutrophil chemotactic factor by TNF-alpha, LPS, and IL-1 beta. Science. 1989 Mar 17;243(4897):1467–1469. doi: 10.1126/science.2648570. [DOI] [PubMed] [Google Scholar]
  60. Yoshimura T., Matsushima K., Tanaka S., Robinson E. A., Appella E., Oppenheim J. J., Leonard E. J. Purification of a human monocyte-derived neutrophil chemotactic factor that has peptide sequence similarity to other host defense cytokines. Proc Natl Acad Sci U S A. 1987 Dec;84(24):9233–9237. doi: 10.1073/pnas.84.24.9233. [DOI] [PMC free article] [PubMed] [Google Scholar]
  61. Yoshimura T., Yuhki N. Neutrophil attractant/activation protein-1 and monocyte chemoattractant protein-1 in rabbit. cDNA cloning and their expression in spleen cells. J Immunol. 1991 May 15;146(10):3483–3488. [PubMed] [Google Scholar]
  62. Youker K., Smith C. W., Anderson D. C., Miller D., Michael L. H., Rossen R. D., Entman M. L. Neutrophil adherence to isolated adult cardiac myocytes. Induction by cardiac lymph collected during ischemia and reperfusion. J Clin Invest. 1992 Feb;89(2):602–609. doi: 10.1172/JCI115626. [DOI] [PMC free article] [PubMed] [Google Scholar]
  63. Zwahlen R. D., Spreng D., Wyder-Walther M. In vitro and in vivo activity of human interleukin-8 in dogs. Vet Pathol. 1994 Jan;31(1):61–66. doi: 10.1177/030098589403100108. [DOI] [PubMed] [Google Scholar]
  64. von Heijne G. The signal peptide. J Membr Biol. 1990 May;115(3):195–201. doi: 10.1007/BF01868635. [DOI] [PubMed] [Google Scholar]

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