title: Protein kinase Cβ is required for lupus development in Sle mice.
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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: University of Rochester School of Medicine, 601 Elmwood Avenue, Rochester, NY 14642, USA.
authors.forename: David
authors.initials: D
authors.lastname: Oleksyn
authors.forename: Mary
authors.initials: M
authors.lastname: Pulvino
authors.forename: Jiyong
authors.initials: J
authors.lastname: Zhao
authors.forename: Ravi
authors.initials: R
authors.lastname: Misra
authors.forename: Aram
authors.initials: A
authors.lastname: Vosoughi
authors.forename: Scott
authors.initials: S
authors.lastname: Jenks
authors.forename: Christopher
authors.initials: C
authors.lastname: Tipton
authors.forename: Frances
authors.initials: F
authors.lastname: Lund
authors.forename: George
authors.initials: G
authors.lastname: Schwartz
authors.forename: Bruce
authors.initials: B
authors.lastname: Goldman
authors.forename: Chandra
authors.initials: C
authors.lastname: Mohan
authors.forename: Kamal
authors.initials: K
authors.lastname: Mehta
authors.forename: Madhu
authors.initials: M
authors.lastname: Mehta
authors.forename: Michael
authors.initials: M
authors.lastname: Leitgets
authors.forename: Ignacio
authors.initials: I
authors.lastname: Sanz
authors.forename: Luojing
authors.initials: L
authors.lastname: Chen
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001402:B-Lymphocytes / Q000166:cytology / Q000187:drug effects*; D002470:Cell Survival / Q000187:drug effects; D004195:Disease Models, Animal; D006801:Humans; D007211:Indoles / Q000494:pharmacology*; D008180:Lupus Erythematosus, Systemic / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D020297:Mice, Congenic; D011493:Protein Kinase C / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D064546:Protein Kinase C beta; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*
chemical_list: D007211:Indoles; D047428:Protein Kinase Inhibitors; D011493:Protein Kinase C; D064546:Protein Kinase C beta; C504878:enzastaurin