The proteasome inhibitor bortezomib inhibits the release of NFκB-inducible cytokines and induces apoptosis of activated T cells from rheumatoid arthritis patients

Clinical and Experimental Rheumatology

W.F. Lems¹  J.W. van der Heijden¹  B.A.C. Dijkmans¹  G. Jansen¹  R.J. Scheper¹  R. Oerlemans¹ 

关键词: Proteasome;    NFκB;    bortezomib;    rheumatoid arthritis;    cytokines;    apoptosis;    methotrexate.;   

DOI  :  

学科分类：医学（综合）

来源: Pacini Editore SpA

【 摘 要 】

OBJECTIVES:The proteasome is a multicatalytic proteinase complex regulating the intracellular breakdown of many proteins, including those mediating the activation of pro-inflammatory signaling pathways (e.g. NFκB), cell proliferation and survival. Conceptually, proteasome inhibitors may therefore elicit potential anti-inflammatory properties by inhibiting these processes and thereby impair the cellular release of pro-inflammatory cytokines such as Tumor Necrosis Factor-α (TNF-α) in RA patients. METHODS: Whole-blood from 19 RA patients (including methotrexate-responsive and non-responsive patients) and 7 healthy volunteers was incubated ex-vivo with the proteasome inhibitor bortezomib after T-cell stimulation with αCD3/CD28. Inhibition of cytokine production by bortezomib was measured after 24 and 72 hours by ELISA. Effects of bortezomib on apoptosis and T-cell activation (CD25 expression) were measured by FACS-analysis. RESULTS:Bortezomib proved to be a rapid (<24 hour) and potent inhibitor of the release of several NFκB-inducible cytokines (including TNF-α, IL-1Β, IL-6 and IL-10) by activated T-cells from healthy volunteers and RA patients, regardless of their clinical responsiveness to methotrexate. Median concentrations of bortezomib required to inhibit TNF-α production by 50% (mIC-50) were 12 nM (range: 8-50 nM) for healthy volunteers and 46 nM (range: 18-60 nM) for RA patients. A reduction of T cell activation and a marked induction of T-cell apoptosis were revealed as late effects after bortezomib incubations beyond 24 hours.CONCLUSIONS:Proteasome inhibitors represented by bortezomib may elicit potential anti-inflammatory properties that deserve further exploration in experimental therapies for RA.

【 授权许可】

Unknown