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We previously found that the novel VR23 proteasome inhibitor not only possesses an effective antitumor activity without causing any ill effects to animals but also reduces side effects caused by a partner drug when used in combination. In this article, we report that VR23, unlike other proteasome inhibitors, exhibits potent anti-inflammatory activity. In the LPS-induced THP-1 monocyte model, VR23 downregulates proinflammatory cytokines IL-1β, TNF-α, IL-6, and IL-8 at a similar efficacy to dexamethasone. In contrast, two well-known proteasome inhibitors, bortezomib and carfilzomib, do not effectively downregulate these proinflammatory cytokines. Data from a study with SW982 synovial cell line and primary human synoviocytes showed that VR23 not only effectively downregulates IL-6 but also inhibits cell migration. Interestingly, the IL-6 downregulation by VR23 was significantly more pronounced in the primary synovial cells from rheumatoid arthritis patients than those from healthy donors, suggesting that VR23 can be selective against rheumatoid arthritis. Finally, VR23 effectively reduces neutrophil migration, TNF-α secretion, and tissue inflammation in mice (female BALB/c strain) with an LPS-induced acute lung injury. Thus, our current data indicate that VR23 can be effective on both acute and chronic inflammatory conditions. Taken together with our previous work, VR23 is not only effective on inflammatory conditions but also applicable to different aspects of cancer control, including the treatment and prevention of tumor development by chronic inflammatory responses., (Copyright © 2020 by The American Association of Immunologists, Inc.)

We have previously shown that increased nuclear accumulation of IkappaBalpha inhibits NF-kappaB activity and induces apoptosis in human leukocytes. In this study, we wanted to explore the possibility that the nucleocytoplasmic distribution of IkappaBalpha can be used as a therapeutic target for the regulation of NF-kappaB-dependent cytokine synthesis. Treatment of LPS-stimulated human U937 macrophages with an inhibitor of chromosome region maintenance 1-dependent nuclear export, leptomycin B, resulted in the increased nuclear accumulation of IkappaBalpha and inhibition of NF-kappaB DNA binding activity, caused by the nuclear IkappaBalpha-p65 NF-kappaB interaction. Surprisingly, however, whereas mRNA expression and cellular release of TNF-alpha, the beta form of pro-IL-1 (IL-1beta), and IL-6 were inhibited by the leptomycin B-induced nuclear IkappaBalpha, IL-8 mRNA expression and cellular release were not significantly affected. Analysis of in vivo recruitment of p65 NF-kappaB to NF-kappaB-regulated promoters by chromatin immunoprecipitation in U937 cells and human PBMCs indicated that although the p65 recruitment to TNF-alpha, IL-1beta, and IL-6 promoters was inhibited by the nuclear IkappaBalpha, p65 recruitment to IL-8 promoter was not repressed. Chromatin immunoprecipitation analyses using IkappaBalpha and S536 phosphospecific p65 NF-kappaB Abs demonstrated that although the newly synthesized IkappaBalpha induced by postinduction repression is recruited to TNF-alpha, IL-1beta, and IL-6 promoters but not to the IL-8 promoter, S536-phosphorylated p65 is recruited to IL-8 promoter, but not to TNF-alpha, IL-1beta, or IL-6 promoters. Together, these data indicate that the inhibition of NF-kappaB-dependent transcription by nuclear IkappaBalpha in LPS-stimulated macrophages is gene specific and depends on the S536 phosphorylation status of the recruited p65 NF-kappaB.