Immunomodulatory Activities of the Benzoxathiole Derivative BOT-4-One Ameliorate Pathogenic Skin Inflammation in Mice

Abstract

T cell-mediated immune responses play an important role in body protection. However, aberrantly activated immune responses are responsible for inflammatory and autoimmune diseases. The regulation of pathological immune responses may be a potential therapeutic strategy for the treatment of these diseases. Despite multiple pharmacological properties of benzoxathiole derivatives have been defined, the molecular mechanisms underlying these properties remain to be clarified. Here, we demonstrated the benzoxathiole derivative 2-cyclohexylimino-6-methyl-6,7-dihydro-5H-benzo[1,3]oxathiol-4-one (BOT-4-one) regulated immune responses and ameliorated experimentally induced inflammatory skin diseases both in vitro and in vivo. BOT-4-one inhibited the differentiation of CD4 T-cell subsets by regulating the expression and production of T cell lineage-specific master transcription factors and cytokines and activating the signal transducer and activator of transcription (STAT) proteins. In addition, BOT-4-one inhibited T-cell receptor (TCR)-mediated Akt and nuclear factor-kappaB (NF-κB) signaling. Topical application of BOT-4-one ameliorated experimentally induced inflammatory skin diseases in mice models such as TNCB-induced contact and atopic dermatitis and IL-23-induced psoriasis-like skin inflammation. Our study demonstrated that BOT-4-one ameliorates inflammatory skin diseases by suppressing the pathogenic CD4 T cell differentiation and the overall immune responses.Journal of Investigative Dermatology accepted article preview online, 30 September 2015. doi:10.1038/jid.2015.384.

Targeting the Microglial NLRP3 Inflammasome and Its Role in Parkinson's Disease

“…A series of acrylate derivative compounds, IFN58 (IC 50 of 74 μM), IFN39 (IC 50 of 10 μM), and BOT‐4‐one (3 μM), a benzoxathiole derivative, inhibit ATPase activity of the NLRP3 inflammasome . BOT‐4‐one (3 μM) modulates ATPase activity of the NLRP3 inflammasome through enhancement of the ubiquitination level of NLRP3 …”

“…[124][125][126] BOT-4-one (3 μM) modulates ATPase activity of the NLRP3 inflammasome through enhancement of the ubiquitination level of NLRP3. [127][128][129] In addition, many promising compounds, such as 2-aminoethaxydiphenyl borate (2-APB), which belongs to a novel boron compound series, and Fc11a-2 and OLT1177, have been reported to inhibit the NLRP3 inflammasome and the release of proinflammatory cytokines. 130 Fc11a-2 which is a benzo[d]imidazole derivative, showed a dose-dependent decrease in IL-1β, IL-18, TNF-α, IL-17A, and IFN-γ in both cellular (30 μM) and animal studies.…”

ATP-Binding and Hydrolysis in Inflammasome Activation

“…The benzoxathiole derivative BOT-4-one (2-cyclohexylimino-6-methyl-6,7-dihydro-5H-1,3-benzoxathiol-4-one) is as an anti-inflammatory alkylating agent which targets NF-κB signaling as well as NLRP3 [ 209 ]. The kinase domain of IKKβ was identified as the probable target of alkylation by BOT-4-one in the NF-κB pathway, with modeling suggesting the nucleophilic addition reaction occurs on Cys179 of IKKβ [ 210 , 211 ]. While BOT-4-one displayed no inhibitory activity toward AIM2 signaling, modest inhibition of NLRC4-mediated IL-1β and caspase-1 maturation was observed, suggesting potential off-target effects even within the NLR family.…”

BOT-4-one attenuates NLRP3 inflammasome activation: NLRP3 alkylation leading to the regulation of its ATPase activity and ubiquitination

“…A novel benzoxathiole derivative, BOT-4-one (2-cyclohexylimino-6-methyl-6,7-dihydro-5 H -benzo[1,3]oxathiol-4-one; Fig. 1a ), which can exhibit anti-cancer effects 16 , has been recently documented as also exhibiting an immunomodulatory activity that alleviates 2,4,6-trinitrochlorobenzene (TNCB)-induced dermatitis and collagen-induced arthritis 17 , 18 . For these anti-inflammatory activities, BOT-4-one has been validated as an NF-κB signaling inhibitor that functions through alkylating target proteins.…”

“…For these anti-inflammatory activities, BOT-4-one has been validated as an NF-κB signaling inhibitor that functions through alkylating target proteins. The kinase domain of IKKβ was identified as the most likely target of alkylation by BOT-4-one in the NF-κB pathway and a plausible nucleophilic addition with Cys179 residue could be modeled as the corresponding alkylation reaction 17 . Therefore, in our study, we aimed to verify the NF-κB pathway-independent potential of BOT-4-one for selective alkylation targeting the ATPase activity of NLRP3 to inhibit the activation of the NLRP3 inflammasome, as in the case of Bay11-7082.…”