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Statins selectively inhibit leukocyte function antigen-1 by binding to a novel regulatory integrin site

Nature Medicine volume 7, pages 687–692 (2001)Cite this article

Abstract

The β2 integrin leukocyte function antigen-1 (LFA-1) has an important role in the pathophysiology of inflammatory and autoimmune diseases. Here we report that statin compounds commonly used for the treatment of hypercholesterolemia selectively blocked LFA-1–mediated adhesion and costimulation of lymphocytes. This effect was unrelated to the statins' inhibition of 3-hydroxy-3-methylglutaryl coenzyme-A reductase; instead it occurred via binding to a novel allosteric site within LFA-1. Subsequent optimization of the statins for LFA-1 binding resulted in potent, selective and orally active LFA-1 inhibitors that suppress the inflammatory response in a murine model of peritonitis. Targeting of the statin-binding site of LFA-1 could be used to treat diseases such as psoriasis, rheumatoid arthritis, ischemia/reperfusion injury and transplant rejection.

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Figure 1: X-ray structure of the lovastatin–I-domain complex and a close-up of the L-site.
Figure 2: Effect of lovastatin and des-oxo-lovastatin on LFA-1–specific T-cell costimulation in the presence or absence of mevalonate.
Figure 3: Effect of des-oxo-lovastatin, cyclosporin A, pravastatin and LFA703 on LFA-1– and VLA-4–induced T-cell costimulation.
Figure 4: Binding of ICAM-1 to immobilized Mac-1 in the presence of statins and an antibody against Mac-1.
Figure 5: Effects of L-site mutations on LFA-1–mediated cell adhesion to ICAM-1.
Figure 6: Inhibition of neutrophil migration in the murine peritonitis model by LFA-1 antagonists.

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References

  1. Carlos, T.M. & Harlan, J.M. Leukocyte-Endothelial adhesion molecules. Blood 84, 2068–2101 (1994).

    CAS  PubMed  Google Scholar 

  2. Dustin, M.L. & Springer T.A. T-cell receptor cross-linking transiently stimulates adhesiveness through LFA-1. Nature 341, 619–624 (1989).

    Article  CAS  Google Scholar 

  3. Campbell, J.J. et al. Chemokines and the arrest of lymphocytes rolling under flow conditions. Science 279, 381–384 (1998).

    Article  CAS  Google Scholar 

  4. Van Seventer, G.A., Shimizu, Y., Horgan, K.J. & Shaw, S. The LFA-1 ligand ICAM-1 provides an important costimulatory signal for T cell receptor-mediated activation of resting T cells. J. Immunol. 144, 4579–4586 (1990).

    CAS  PubMed  Google Scholar 

  5. Grakoui, A. et al. The immunological synapse: a molecular machine controlling T cell activation. Science 285, 221–227 (1999).

    Article  CAS  Google Scholar 

  6. Nakakura, E.K. et al. Long-term survival of solid organ allografts by brief anti-lymphocyte function-associated antigen-1 monoclonal antibody monotherapy. Transplantation 62, 547–552 (1996).

    Article  CAS  Google Scholar 

  7. Poston, R.S. et al. Effects of humanized monoclonal antibody to rhesus CD11a in rhesus monkey cardiac allograft recipients. Transplantation 69, 2005–2013 (2000).

    Article  CAS  Google Scholar 

  8. Martin, X. et al. Protective effect of an anti-LFA 1 monoclonal antibody (odulimomab) on renal damage due to ischemia and kidney autotransplantation. Transplant. Proc. 32, 481 (2000).

    Article  CAS  Google Scholar 

  9. Scheynius, A., Camp, R.L. & Pure, E. Unresponsiveness to 2,4-dinitro-1-fluoro-benzene after treatment with monoclonal antibodies to leukocyte function-associated molecule-1 and intercellular adhesion molecule-1 during sensitization. J. Immunol. 156, 1804–1809 (1996).

    CAS  PubMed  Google Scholar 

  10. Issekutz, A.C. Adhesion molecules mediating neutrophil migration to arthritis in vivo and across endothelium and connective tissue barriers in vitro. Inflamm. Res. 47, S123–S132 (1998).

    Article  CAS  Google Scholar 

  11. Krueger, J. et al. Anti-CD11a treatment for psoriasis concurrently increases circulating T-cells and decreases plaque T-cells, consistent with inhibition of cutaneous T-cell trafficking. J. Invest. Dermatol. 115, 333 (2000).

    Article  CAS  Google Scholar 

  12. Fischer, A. et al. Reduction of graft failure by a monoclonal antibody (anti-LFA-1–CD11a) after HLA nonidentical bone marrow transplantation in children with immunodeficiencies, osteopetrosis and Fanconi's anemia: a European Group for Immunodeficiency/European Group for Bone Marrow Transplantation report. Blood 77, 249–456 (1991).

    CAS  PubMed  Google Scholar 

  13. Hourmant, M. et al. A randomized multicenter trial comparing leukocyte function-associated antigen-1 monoclonal antibody with rabbit antithymocyte globulin as induction treatment in first kidney transplantations. Transplantation 62, 1565–1570 (1996).

    Article  CAS  Google Scholar 

  14. Kallen, J. et al. Structural basis for LFA-1 inhibition upon lovastatin binding to the CD11a I-domain. J. Mol. Biol. 292, 1–9 (1999).

    Article  CAS  Google Scholar 

  15. Corsini, A., Maggi, F.M. & Catapano, A.L. Pharmacology of competitive inhibitors of HMG-CoA reductase. Pharmacol. Res. 31, 9–27 (1995).

    Article  CAS  Google Scholar 

  16. Maron, D.J., Fazio, S. & Linton, M.F. Current perspectives on statins. Circulation 101, 207–213 (2000).

    Article  CAS  Google Scholar 

  17. Katznelson, S. & Kobashigawa, J.A. Dual roles of HMG-CoA reductase inhibitors in solid organ transplantation: Lipid lowering and immunosuppression. Kidney Int. 48, S112–S115 (1995).

    Google Scholar 

  18. Wenke, K. et al. Simvastatin reduces graft vessel disease and mortality after heart transplantation. Circulation 96, 1398–1402 (1997).

    Article  CAS  Google Scholar 

  19. Kobashigawa, J.A. et al. Effect of pravastatin on outcomes after cardiac transplantation. N. Engl. J. Med. 333, 621–627 (1995).

    Article  CAS  Google Scholar 

  20. Duggan, D.E. & Vickers, S. Physiological disposition of HMG-CoA-reductase inhibitors. Drug Metab. Rev. 22, 333–362 (1990).

    Article  CAS  Google Scholar 

  21. Legge, G.B. et al. NMR solution structure of the inserted domain of human leukocyte function associated antigen-1. J. Mol. Biol. 295, 1251–1264 (2000).

    Article  CAS  Google Scholar 

  22. Lee, J.O., Rieu, P., Arnaout, M.A. & Liddington, R. Crystal structure of the A domain from the alpha subunit of integrin CR3 (CD11b/CD18). Cell 80, 631–638 (1995).

    Article  CAS  Google Scholar 

  23. Qu, A. & Leahy, D.J. Crystal structure of the I-domain from the CD11a/CD18 (LFA-1, αL β2) integrin. Proc. Natl. Acad. Sci. USA 92, 10277–10281 (1995).

    Article  CAS  Google Scholar 

  24. Kurakata, S., Kada, M., Shimada, Y., Komai, T. & Nomoto, K. Effects of different inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, pravastatin sodium and simvastatin, on sterol synthesis and immunological functions in human lymphocytes in vitro. Immunopharmacol. 34, 51–61 (1996).

    Article  CAS  Google Scholar 

  25. Emsley, J., Knight, C.G., Farndale R.W., Barnes M.J. & Liddington, R.C. Structural basis of collagen recognition by integrin α2β1 . Cell 100, 47–56 (2000).

    Article  Google Scholar 

  26. Leitinger, B. & Hogg, N. From crystal clear ligand binding to designer I domains. Nature Struct. Biol. 7, 614–616 (2000).

    Article  CAS  Google Scholar 

  27. Kelly, T.A. et al. A small molecule antagonist of LFA-1-mediated cell adhesion. J. Immunol. 163, 5173–5177 (1999).

    CAS  PubMed  Google Scholar 

  28. Liu, G. et al. Discovery of novel p-arylthio cinnamides as antagonists of leukocyte function-associated antigen-1/intracellular adhesion molecule-1 interaction. 1. Identification of an additional binding pocket based on an anilino diaryl sulfide lead. J. Med. Chem. 43, 4025–4040 (2000).

    Article  CAS  Google Scholar 

  29. Endres, M. et al. Stroke protection by 3-hydroxy-3-methylglutaryl (HMG)-CoA reductase inhibitors mediated by endothelial nitric oxide synthase. Proc. Natl. Acad. Sci. USA 95, 8880–8885 (1998).

    Article  CAS  Google Scholar 

  30. Mundy, G. et al. Stimulation of bone formation in vitro and in rodents by statins. Science 286, 1946–1949 (1999).

    Article  CAS  Google Scholar 

  31. Kwak, B., Mulhaupt, F., Myit, S. & Mach, F. Statins as a newly recognized type of immunomodulators. Nature Med. 6, 1399–1402 (2000).

    Article  CAS  Google Scholar 

  32. Romano, M. et al. Inhibition of monocyte chemotactic protein-1 synthesis by statins. Lab. Invest. 80, 1095–1100 (2000).

    Article  CAS  Google Scholar 

  33. Huth, J.R. et al. NMR and mutagenesis evidence for an I domain allosteric site that regulates lymphocyte function-associated antigen ligand binding. Proc. Natl. Acad. Sci. USA 97, 5231–5236 (2000).

    Article  CAS  Google Scholar 

  34. Mousa, S.A. &. Cheresh, D.A. Recent advances in cell adhesion molecules and extracellular matrix proteins: potential clinical implications. Drug Discov. Today 2, 187–199 (1997).

    Article  CAS  Google Scholar 

  35. de Fougerolles, A.R. et al. Regulation of inflammation by collagen-binding integrins α1β1 and α2β1 in models of hypersensitivity and arthritis. J. Clin. Invest. 105, 721–729 (2000).

    Article  CAS  Google Scholar 

  36. Diamond, M.S. et al. ICAM-1 (CD54): A counter-receptor for Mac-1 (CD11b/CD18). J. Cell. Biol. 111, 3129–3139 (1990).

    Article  CAS  Google Scholar 

  37. Palmer III, A.G., Cavanagh, J., Wright, P.E. & Rance, M. Sensitivity improvement in proton-detected two-dimensional heteronuclear correlation NMR spectrocsopy. J. Magn. Reson. 93, 151–170 (1991).

    CAS  Google Scholar 

  38. Shum, Y.Y. et al. Development, validation, and interlaboratory comparison of an HMG-CoA reductase inhibition assay for quantitation of artovastatin in plasma matrices. Ther. Drug Monit. 20, 41–49 (1998).

    Article  CAS  Google Scholar 

  39. Deng, W.P. & Nickoloff, J.A. Site-directed mutagenesis of virtually any plasmid by eliminating a unique site. Anal. Biochem. 200, 81–88 (1992).

    Article  CAS  Google Scholar 

  40. Kamata, T., Wright, R. & Takada, Y. Critical threonine and aspartic acid residues within the I domains of beta 2 integrins for interactions with intercellular adhesion molecule 1 (ICAM-1) and C3bi. J. Biol. Chem. 270, 12531–12535 (1995).

    Article  CAS  Google Scholar 

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Acknowledgements

We thank J.P. Evenou for the establishment of the HMG-CoA reductase assay and testing the compounds; L. Michel and C. Wilt for technical assistance; and A.G. Schmidt for critical reading of the manuscript.

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Authors and Affiliations

  1. Novartis Pharma AG, Preclinical Research, Basel, Switzerland

    Gabriele Weitz-Schmidt, Karl Welzenbach, Volker Brinkmann, Joerg Kallen, Christian Bruns, Sylvain Cottens & Ulrich Hommel

  2. Department of Vascular Biology, The Scripps Research Institute, La Jolla, California, USA

    Tetsji Kamata & Yoshikazu Takada

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Correspondence to Gabriele Weitz-Schmidt.

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Weitz-Schmidt, G., Welzenbach, K., Brinkmann, V. et al. Statins selectively inhibit leukocyte function antigen-1 by binding to a novel regulatory integrin site. Nat Med 7, 687–692 (2001). https://doi.org/10.1038/89058

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