Protein Kinase C[beta] Is Required for Lupus Development in Sle Mice

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