Proteasome inhibitors as experimental therapeutics of autoimmune diseases

Abstract

Current treatment strategies for rheumatoid arthritis (RA) consisting of disease-modifying anti-rheumatic drugs or biological agents are not always effective, hence driving the demand for new experimental therapeutics. The antiproliferative capacity of proteasome inhibitors (PIs) has received considerable attention given the success of their first prototypical representative, bortezomib (BTZ), in the treatment of B cell and plasma cell-related hematological malignancies. Therapeutic application of PIs in an autoimmune disease setting is much less explored, despite a clear rationale of (immuno) proteasome involvement in (auto)antigen presentation, and PIs harboring the capacity to inhibit the activation of nuclear factor-κB and suppress the release of pro-inflammatory cytokines such as tumor necrosis factor alpha and interleukin-6. Here, we review the clinical positioning of (immuno) proteasomes in autoimmune diseases, in particular RA, systemic lupus erythematosus, Sjögren's syndrome and sclerodema, and elaborate on (pre)clinical data related to the impact of BTZ and next generation PIs on immune effector cells (T cells, B cells, dendritic cells, macrophages, osteoclasts) implicated in their pathophysiology. Finally, factors influencing long-term efficacy of PIs, their current (pre)clinical status and future perspectives as anti-inflammatory and anti-arthritic agents are discussed.

Figure 1

Role of proteasomes in protein degradation and nuclear factor-κ B activation. (A) After initial synthesis, proteins at the end of their (functional) life-span, or damaged/misfolded proteins, are subject to degradation after conjugating with an ubiquitin (Ub) tag. Recognition by the proteasome initiates protein degradation to smaller peptides, which are further processed by aminopeptidases either to free amino acid for renewed protein synthesis or to trimmed peptides presented by major histocompatibility complex class I molecules. (B) Mechanism of blockade of nuclear factor (NF)-κB activation by the proteasome inhibitor bortezomib. This inhibitory effect prevents the degradation of the natural inhibitor of NF-κB (that is, IκB) along with nuclear translocation of p50/p65 and transcription of pro-inflammatory cytokines. IL, interleukin; TNF, tumor necrosis factor.

Figure 2

Subunit composition of constitutive and immunoproteasomes. (A) 20S core proteasome. (B) Fully assembled proteasome. Coloured subunits represent catalytic subunits. IFN, interferon; TNF, tumor necrosis factor.

Figure 3

Chemical structures of proteasome inhibitors. Asterisks indicate that the compound has not been evaluated for potential anti-inflammatory properties.