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

Gabriele Weitz-Schmidt, Karl Welzenbach, Volker Brinkmann, Tetsji Kamata, Joerg Kallen, Christian Bruns, Sylvain Cottens, Yoshikazu Takada, Ulrich Hommel

Research output: Contribution to journalArticle

903 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)687-692
Number of pages6
JournalNature Medicine
Volume7
Issue number6
DOIs
Publication statusPublished - 2001
Externally publishedYes

Fingerprint

Hydroxymethylglutaryl-CoA Reductase Inhibitors
HLA Antigens
Integrins
Antigens
Allosteric Site
Transplants
Lymphocytes
Graft Rejection
Hypercholesterolemia
Reperfusion Injury
Peritonitis
Psoriasis
Autoimmune Diseases
Rheumatoid Arthritis
Oxidoreductases
Adhesion
Binding Sites

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

Cite this

Weitz-Schmidt, G., Welzenbach, K., Brinkmann, V., Kamata, T., Kallen, J., Bruns, C., ... Hommel, U. (2001). Statins selectively inhibit leukocyte function antigen-1 by binding to a novel regulatory integrin site. Nature Medicine, 7(6), 687-692. https://doi.org/10.1038/89058

Statins selectively inhibit leukocyte function antigen-1 by binding to a novel regulatory integrin site. / Weitz-Schmidt, Gabriele; Welzenbach, Karl; Brinkmann, Volker; Kamata, Tetsji; Kallen, Joerg; Bruns, Christian; Cottens, Sylvain; Takada, Yoshikazu; Hommel, Ulrich.

In: Nature Medicine, Vol. 7, No. 6, 2001, p. 687-692.

Research output: Contribution to journalArticle

Weitz-Schmidt, G, Welzenbach, K, Brinkmann, V, Kamata, T, Kallen, J, Bruns, C, Cottens, S, Takada, Y & Hommel, U 2001, 'Statins selectively inhibit leukocyte function antigen-1 by binding to a novel regulatory integrin site', Nature Medicine, vol. 7, no. 6, pp. 687-692. https://doi.org/10.1038/89058
Weitz-Schmidt G, Welzenbach K, Brinkmann V, Kamata T, Kallen J, Bruns C et al. Statins selectively inhibit leukocyte function antigen-1 by binding to a novel regulatory integrin site. Nature Medicine. 2001;7(6):687-692. https://doi.org/10.1038/89058
Weitz-Schmidt, Gabriele ; Welzenbach, Karl ; Brinkmann, Volker ; Kamata, Tetsji ; Kallen, Joerg ; Bruns, Christian ; Cottens, Sylvain ; Takada, Yoshikazu ; Hommel, Ulrich. / Statins selectively inhibit leukocyte function antigen-1 by binding to a novel regulatory integrin site. In: Nature Medicine. 2001 ; Vol. 7, No. 6. pp. 687-692.
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