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Statins as a newly recognized type of immunomodulator

Abstract

Inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, or statins, are effective lipid-lowering agents, extensively used in medical practice1,2,3. Statins have never been shown to be involved in the immune response, although a report has indicated a better outcome of cardiac transplantation in patients under Pravastatin therapy4. Major histocompatibility complex class II (MHC-II) molecules are directly involved in the activation of T lymphocytes and in the control of the immune response. Whereas only a limited number of specialized cell types express MHC-II constitutively, numerous other cells become MHC-II positive upon induction by interferon γ (IFN-γ)5. This complex regulation is under the control of the transactivator CIITA (refs 6,7). Here we show that statins act as direct inhibitors of induction of MHC-II expression by IFN-γ and thus as repressors of MHC-II-mediated T-cell activation. This effect of statins is due to inhibition of the inducible promoter IV of the transactivator CIITA and is observed in several cell types, including primary human endothelial cells (ECs) and monocyte-macrophages (Mφ). It is of note that this inhibition is specific for inducible MHC-II expression and does not concern constitutive expression of CIITA and MHC-II. In repressing induction of MHC-II, and subsequent T-lymphocyte activation, statins therefore provide a new type of immunomodulation. This unexpected effect provides a scientific rationale for using statins as immunosuppressors, not only in organ transplantation but in numerous other pathologies as well.

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Figure 1: Statins decrease IFN-γ induced MHC-II protein expression on human endothelial cells and macrophages.
Figure 2: Effect of statins on IFN-γ induced MHC-II expression is mediated by the transactivator CIITA.
Figure 3: Functional consequences of inhibition of MHC-II antigens by statins on T-lymphocyte activation.
Figure 4: Statins specifically decreased the expression of promoter IV of the transactivator CIITA on a transcriptional level.

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References

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

    Article  CAS  Google Scholar 

  2. Vaughan, C.J., Gotto, A.M. & Basson, C.T. The evolving role of statins in the management of atherosclerosis. J. Am. Coll. Cardiol. 35, 1–10 (2000).

    Article  CAS  Google Scholar 

  3. Pedersen, T.R. Statin trials and goals of cholesterol-lowering therapy after AMI. Am. Heart. J. 138, 177–182 (1999).

    Article  Google Scholar 

  4. 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 

  5. Mach, B., Steimle, V., Martinez-Soria, E. & Reith, W. Regulation of MHC class II genes: lessons from a disease. Annu. Rev. Immunol. 14, 301–331 (1996).

    Article  CAS  Google Scholar 

  6. Steimle, V. et al. Complementation cloning of an MHC class II transactivator mutated in hereditary MHC class II deficiency (or bare lymphocyte syndrome). Cell 75, 135–146 (1993).

    Article  CAS  Google Scholar 

  7. Steimle, V. et al. Regulation of MHC class II expression by interferon-gamma mediated by the transactivator gene CIITA. Science 265, 106–109 (1994).

    Article  CAS  Google Scholar 

  8. Hebert, P.R., Gaziano, J.M., Chan, K.S. & Hennekens, C.H. Cholesterol lowering with statin drugs, risk of stroke, and total mortality. An overview of randomized trials. JAMA 278, 313–321 (1997).

    Article  CAS  Google Scholar 

  9. Vaughan, CJ., Murphy, M.B. & Buckley, B.M. Statins do more than just lower cholesterol. Lancet 348, 1079–1082 (1996).

    Article  CAS  Google Scholar 

  10. Masternak, K. et al. A gene encoding a novel RFX-associated transactivator is mutated in the majority of MHC class II deficiency patients. Nat. Genet. 20, 273–277 (1998).

    Article  CAS  Google Scholar 

  11. Muhlethaler-Mottet, A. et al. Expression of MHC Class II molecules in different cellular and functional compartments is controlled by differential usage of multiple promoters of transactivator CIITA. EMBO J. 16, 2851–2860 (1997).

    Article  CAS  Google Scholar 

  12. Muhlethaler-Mottet, A. et al. Activation of MHC Class II transactivator CIITA by interferon gamma requires cooperative interaction between Stat1 and USF-1. Immunity 8, 157–166 (1998).

    Article  CAS  Google Scholar 

  13. Otten, L.A., Steimle, V., Bontron, S. & Mach, B. Quantitation control of MHC Class II expression by the transactivator CIITA. Eur. J. Immunol. 82, 473–478 (1998).

    Article  Google Scholar 

  14. Lee, Y.J. & Benveniste, E.N. Stat1 alpha expression is involved in IFN-gamma induction of the class II transactivator and class II MHC genes. J. Immunol. 157, 1559–1568 (1996).

    CAS  PubMed  Google Scholar 

  15. Mach, F. et al. Functional CD40 is expressed on human vascular endothelial cells, smooth muscle cells, and macrophage: implication for CD40-CD40 ligand signaling in atherosclerosis. Proc. Natl. Acad. Sci. USA 94, 1931–1936 (1997).

    Article  CAS  Google Scholar 

  16. Arrighi, J.F., Hauser, C., Chapuis, B., Zubler, R.H. & Kindler, V. Long-term culture of human CD34(+) progenitors with FLT3-ligand, thrombopoietin, and stem cell factor induces extensive amplification of a CD34(−)CD14(−) and a CD34(−)CD14(+) dendritic cell precursor. Blood 93, 2244–2252 (1999).

    CAS  PubMed  Google Scholar 

  17. Kovalik, J.P., Singh, N., Mendiratta, S.K., Martin, W.D., Ignatowicz, L. & Van Kaer, L. The alloreactive and self-restricted CD4+ T cell response directed against a single MHC Class II/peptide combination. J. Immunol. 165, 1285–1293 (2000).

    Article  CAS  Google Scholar 

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Acknowledgements

This work was supported by the Swiss National Scientific Research Funds (grant 3800-054965.98/1) to F.M and to NovImmune S.A. We are grateful to A. Muhlethaler-Mottet and W. Reith (Department of Genetic and Microbiology, Geneva) for providing us with the human MHC and CIITA probes, to V. Kindler (Division of Hematology, Geneva) for human dendritic cells, and to N. Rufer (Immunology Division, Geneva) for mixed-lymphocyte reactions.

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Correspondence to François Mach.

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Kwak, B., Mulhaupt, F., Myit, S. et al. Statins as a newly recognized type of immunomodulator. Nat Med 6, 1399–1402 (2000). https://doi.org/10.1038/82219

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