Protein kinase Cβ is required for lupus development in sle mice

David Oleksyn, Mary Pulvino, Jiyong Zhao, Ravi Misra, Aram Vosoughi, Scott Jenks, Christopher Tipton, Frances Lund, George Schwartz, Bruce Goldman, Chandra Mohan, Kamal Mehta, Madhu Mehta, Michael Leitgets, Ignacio Sanz, Luojing Chen

Research output: Contribution to journalArticle

11 Scopus citations

Abstract

Objective To evaluate the requirement for protein kinase Cβ (PKCβ) in the development of lupus in mice, and to explore the potential of targeting PKCβ as a therapeutic strategy in lupus. Methods Congenic mice bearing the disease loci Sle1 or Sle1 and Sle3, which represent different stages of severity in the development of lupus, were crossed with PKCβ-deficient mice. The effect of PKCβ deficiency in lupus development was analyzed. In addition, the effects of the PKCβ-specific inhibitor enzastaurin on the survival of B cells from mice with lupus and human 9G4-positive B cells as well as the in vivo effect of enzastaurin treatment on the development of lupus in Sle mice were investigated. Results In Sle mice, PKCβ deficiency abrogated lupus-associated phenotypes, including high autoantibody levels, proteinuria, and histologic features of lupus nephritis. Significant decreases in spleen size and in the peritoneal B-1 cell population, reduced numbers of activated CD4 T cells, and normalized CD4:CD8 ratios were observed. PKCβ deficiency induced an anergic B cell phenotype and preferentially inhibited autoreactive plasma cells and autoantibodies in mice with lupus. Inhibition of PKCβ enhanced apoptosis of both B cells from Sle mice and human autoreactive B cells (9G4 positive). Treatment of Sle mice with the PKCβ-specific inhibitor enzastaurin prevented the development of lupus. Conclusion This study identifies PKCβ as a central mediator of lupus pathogenesis, suggesting that PKCβ represents a promising therapeutic target for the treatment of systemic lupus erythematosus. Moreover, the results indicate the feasibility of using a PKCβ inhibitor for the treatment of lupus.

Original languageEnglish (US)
Pages (from-to)1022-1031
Number of pages10
JournalArthritis and rheumatism
Volume65
Issue number4
DOIs
StatePublished - Apr 2013

ASJC Scopus subject areas

  • Immunology and Allergy
  • Rheumatology
  • Immunology
  • Pharmacology (medical)

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    Oleksyn, D., Pulvino, M., Zhao, J., Misra, R., Vosoughi, A., Jenks, S., Tipton, C., Lund, F., Schwartz, G., Goldman, B., Mohan, C., Mehta, K., Mehta, M., Leitgets, M., Sanz, I., & Chen, L. (2013). Protein kinase Cβ is required for lupus development in sle mice. Arthritis and rheumatism, 65(4), 1022-1031. https://doi.org/10.1002/art.37825