PIM kinase activity is required for B cell function in vitro and in vivo (109.5)

Abstract

Abstract The PIM family of serine/threonine kinases has roles in proliferation, differentiation, and cell survival. In lymphocytes, their activity is regulated by inducible expression following cytokine or antigen receptor signaling. Using small molecule inhibitors, we have examined the role of PIM1/3 kinases in B cells in vitro and in vivo and in the MRL/LPR model of lupus. PIM kinases were expressed 1-3 hours after B cell activation with anti-IgM or anti-CD40 but not BAFF. Inhibition of PIM-1/3 kinase activity decreased anti-IgM- and anti-CD40-induced B cell proliferation without inducing apoptosis. AR-254 also prevented IL-4-, and IFNy-induced B cell survival, but had no affect on BAFF-induced B cell survival consistent with the inability of BAFF to upregulate PIM expression. AR-770 administration in the HEL immunization model resulted in a 90% reduction of HEL-specific IgG2a and IgG3, but had no effect on IgG1 suggesting a role for PIM kinases in IFNy-mediated class switching. In the MRL/MpJ-Fas<lpr> lupus model, mice treated with AR-770 had >90% reduction in proteinuria AUC, normalized anti-dsDNA antibody titers and ~80% decrease in kidney glomerulo- and interstitial nephritis as well as vessel and protein cast formation. Under specific conditions, Taken together, the data suggests that inhibition of PIM kinases may be a useful strategy for patients with B cell-mediated diseases such as lupus.