Abstract
Systemic lupus erythematosus (SLE) is a chronic multisystemic autoimmune disease with an unknown etiology. Recently, it has been elucidated that dysregulated histone deacetylase (HDAC) activity is related to the pathogenesis of inflammatory and autoimmune diseases. Broad-spectrum HDAC inhibitors are effective for the treatment of allergy, cancer, and autoimmune diseases, but they have several adverse side effects. Thus, the purpose of this study was to evaluate the effects of a novel HDAC 6-specific inhibitor, CKD-506, in a murine SLE model. CKD-506 significantly improved survival rate and significantly decreased the incidence of severe proteinuria, blood urea nitrogen, kidney inflammation, and glomerular infiltration of IgG and C3. In addition, CKD 506 reduced the proportions of CD138+ plasma cells, CD4−CD8− T cells, and CD25+ cells and the Th1/Th2 ratio in the spleen. CKD-506 significantly reduced inflammatory cytokines such as IL-10, IL-15, IL-17, TNF-α, and IFN-inducible protein (IP-10) and significantly increased TGF-β in serum. CKD-506 also significantly reduced IFN-γ, IL-1β, IL-4, IL-6, IP-10, MCP-1, and CCL4 levels in kidney. CKD-506 decreased the production of various pro-inflammatory cytokines and chemokines in the serum and kidneys, resulting in inhibition of cell migration and suppression of lupus nephritis without adverse effects.
Highlights
Systemic lupus erythematosus (SLE) is a chronic multisystemic autoimmune disease that occurs when body tissues and organs are attacked by its own immune system; in SLE, anti-nuclear antibodies are developed, and circulating antigen-antibody complexes are produced and lodge in small vessels and various organ systems, especially in the basement membrane zone of the skin and kidney
To confirm the intracellular inhibitory activity of CKD-506, the effect of CKD-506 on the acetylation of tubulin, a major HDAC6 target protein, and histone H4 was analyzed with human peripheral blood mononuclear cells (PBMC) (Fig. 1B)
CKD-506 induced the acetylation of α tubulin from 30 nM without affecting the acetylation of histone H4 which is not a target protein of HDAC6
Summary
Systemic lupus erythematosus (SLE) is a chronic multisystemic autoimmune disease that occurs when body tissues and organs are attacked by its own immune system; in SLE, anti-nuclear antibodies are developed, and circulating antigen-antibody complexes are produced and lodge in small vessels and various organ systems, especially in the basement membrane zone of the skin and kidney. NZB/W F1 female mice show a spontaneous autoimmune disease process similar to the pathogenesis of human SLE; they produce anti-nuclear antibodies, including anti-double-stranded (ds) DNA antibodies, and develop severe immune complex-mediated glomerulonephritis. These mice die of renal failure by the age of 10–12 months[3]. Pan HDAC inhibitors showed excellent efficacy in the treatment of allergy, cancer, and autoimmune diseases[12,13,14] Their significant adverse effects such as fatigue, anorexia, nausea, vomiting, diarrhea, weight loss, asthenia, thrombocytopenia, neutropenia, anemia, and alteration of serum biochemistry profiles significantly limited its clinical application in chronic indications such as SLE12. It has been proposed that HDAC subtype selective inhibitors, which have fewer adverse effects than Pan HDAC inhibitors, can be used for treatment of chronic diseases; the emerging trend is to identify HDAC isozyme selective inhibitor with both immunomodulatory activity and improved safety profile
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