Protein kinase Cβ is required for lupus development in Sle mice

Arthritis Rheum. 2013 Apr;65(4):1022-31. doi: 10.1002/art.37825.

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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Apoptosis / drug effects
  • B-Lymphocytes / cytology
  • B-Lymphocytes / drug effects*
  • Cell Survival / drug effects
  • Disease Models, Animal
  • Humans
  • Indoles / pharmacology*
  • Lupus Erythematosus, Systemic / drug therapy
  • Lupus Erythematosus, Systemic / genetics
  • Lupus Erythematosus, Systemic / metabolism*
  • Mice
  • Mice, Congenic
  • Protein Kinase C / antagonists & inhibitors
  • Protein Kinase C / genetics
  • Protein Kinase C / metabolism*
  • Protein Kinase C beta
  • Protein Kinase Inhibitors / pharmacology*

Substances

  • Indoles
  • Protein Kinase Inhibitors
  • Protein Kinase C
  • Protein Kinase C beta
  • enzastaurin