Protein kinase Cß is required for lupus development in Sle mice.

OBJECTIVE: To evaluate the requirement for protein kinase Cß (PKCß) in the development of lupus in mice, and to explore the potential of targeting PKCß 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 PKCß-deficient mice. The effect of PKCß deficiency in lupus development was analyzed. In addition, the effects of the PKCß-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, PKCß 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. PKCß deficiency induced an anergic B cell phenotype and preferentially inhibited autoreactive plasma cells and autoantibodies in mice with lupus. Inhibition of PKCß enhanced apoptosis of both B cells from Sle mice and human autoreactive B cells (9G4 positive). Treatment of Sle mice with the PKCß-specific inhibitor enzastaurin prevented the development of lupus. CONCLUSION: This study identifies PKCß as a central mediator of lupus pathogenesis, suggesting that PKCß represents a promising therapeutic target for the treatment of systemic lupus erythematosus. Moreover, the results indicate the feasibility of using a PKCß inhibitor for the treatment of lupus.