Volume 10 Supplement 1

2011 Pediatric Rheumatology Symposium: Abstracts

Open Access

Simvastatin and ROCK inhibition in Th0 and Th17 systems

  • Josephine Isgro2,
  • Li Song1,
  • Sanjay Gupta1 and
  • Alessandra B Pernis1
Pediatric Rheumatology201210(Suppl 1):A112

https://doi.org/10.1186/1546-0096-10-S1-A112

Published: 13 July 2012

Purpose

The deregulation of the Def6-ROCK2-IRF4 axis in murine models results in both lupus-like and rheumatoid arthritis-like disease characterized by increased IL-17 and IL-21 production that is ameliorated by ROCK inhibition. A known beneficial pleiotropic effect of statins is inhibition of ROCK activation via their effect on RhoA activation. Statins have also been reported to decrease IL-17 and IL-21 production in T cells. Whether statins exert their inhibitory effects by interfering with the ROCK2-IRF-4 interaction in CD4+ T cells is unknown. The aim of the present study is to investigate whether statins can inhibit the ROCK pathway in CD4+ T cells and inhibit IL-17 and IL-21 production.

Methods

Purified CD4+ T cells from the spleens and lymph nodes of wild type and Def6-deficient DO11.10 transgenic mice were stimulated with αCD3 and αCD28 in the presence/absence of simvastatin (1-10μM) with and without the known ROCK inhibitor, Y-27632 (10-30μM). Supernatants were collected and IL-17 and IL-21 production analyzed by ELISA.

Results

As previously reported, Def6-deficient CD4+ T cells secreted significantly higher levels of IL-17 and IL-21 when stimulated as compared to wild type controls, which was ameliorated by addition of the ROCK inhibitor, Y-27632. Simvastatin significantly decreased the concentrations of IL-17 and IL-21 at all tested concentrations in a dose dependent manner (p<.05). At lower concentrations of simvastatin (<2.5μM), the addition of Y-27632 further decreased cytokine production.

Conclusion

These data suggest that simvastatin can interfere with the ROCK pathway in CD4+ T cells and inhibit IL-17 and IL-21 production in a murine model of autoimmunity. As statins and ROCK inhibitors have distinct targets, our data furthermore suggest that combination therapy with a statin and a ROCK inhibitor may be more effective than monotherapy. Furthermore, we speculate that the decrease in cytokines is linked to a decrease in the phosphorylation status of IRF4 and its ability to target the promoters of these cytokines.

Disclosure

Josephine Isgro: None; Li Song: None; Sanjay Gupta: None; Alessandra B. Pernis: None.

Authors’ Affiliations

(1)
Hospital for Special Surgery
(2)
Morgan Stanley Children's Hospital of New York Presbyterian, Columbia University Medical Center

Copyright

© Isgro et al; licensee BioMed Central Ltd. 2012

This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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