Purpose: Proteasome inhibitors have been proposed as a new therapy for SLE because of their effects on plasma cells. Animal studies have shown that bortezomib, a dipeptide boronate that targets the constitutive and immunoproteasome, induces apoptosis of short-lived and long-lived plasma cells via induction of the unfolded protein response, and is also able to decrease autoantibody production and prolong survival. Since proteasome inhibitors block activation of NFkappaB by preventing degradation of IkappB, they should also have effects on cellular activation such as alpha interferon production after stimulation of toll-like receptors. Bortezomib is approved for the treatment of multiple myeloma but its use in non-malignant conditions may be limited due to unacceptable toxicities such as painful peripheral neuropathy. Because of this problem, new proteasome inhibitors are being developed. Carfilzomib is a peptide epoxyketone proteasome inhibitor that has greater selectivity for the proteasome than bortezomib and is currently in phase 2 clinical studies in myeloma. PR-957 is a novel, immunoproteasome selective inhibitor of the same chemical class as carfilzomib.
Methods: The effects of carfilzomib and PR-957, were compared to bortezomib in PBMCs and B-cells. Alpha interferon was assayed by ELISA, immunoglobulin production by ELISPOTS, and proliferation by CFSE/flow cytometry.
Results: Induction of alpha interferon production by PBMCs treated with polyIC or with ODN2216 activating respectively TLR-3 or TLR-9 was dramatically inhibited by all three proteasome inhibitors. (See below.) The effects of these proteasome inhibitors on B cell activation by IL-2 and CpG were also examined. B cell proliferation and IgM or IgG antibody secreting cells were inhibited by all three proteasome inhibitors. (Data not shown.).
Conclusions These results demonstrate for the first time that proteasome inhibitors are able to block production of alpha interferon induced by stimulation of toll-like receptors, and also show that proteasome inhibitors can block B cell proliferation and differentiation. Furthermore, activity with PR-957 suggests that the effects of carfilzomib and bortezomib are mediated through immunoproteasome inhibition. Thus, the potential beneficial effects of proteasome inhibitors in SLE may work through multiple mechanisms.