Abstract
Interferon-γ (IFN-γ), a critical inflammatory cytokine, is primarily produced by T helper 1 (Th1) cells and accelerates the pathogenesis of inflammatory colitis. Pharmacological suppression of IFN-γ production attenuates dysregulated inflammatory responses and may be beneficial for treating inflammatory disease. In this study, we aimed to discover potent anti-inflammatory compounds that suppress IFN-γ production and found that the novel benzoxazole derivatives, 2-((3,4-dichlorophenyl) amino) benzo[d]xazol-5-ol (DCPAB) and 2-((3,4-hydroxyphenyl) amino) benzo[d]xazol-5-ol (HPAB), suppressed IFN-γ production by T cells. Treatment of CD4+ T cells with DCPAB and HPAB selectively inhibited Th1 cell development, and DCPAB more potently suppressed IFN-γ than HPAB did. Interestingly, DCPAB and HPAB significantly suppressed the expression of T-box containing protein expressed in T cells (T-bet) that activates IFN-γ gene transcription. DCPAB additionally suppressed transcriptional activity of T-bet on IFN-γ gene promoter, whereas HPAB had no effect on T-bet activity. IFN-γ suppressive activity of DCPAB and HPAB was impaired in the absence of T-bet but was retrieved by the restoration of T-bet in T-bet-deficient T cells. Furthermore, DCPAB and HPAB attenuated inflammatory colitis development that was induced by CD4+ T cells in vivo. We suggest that the novel benzoxazole derivatives, DCPAB and HPAB, may have therapeutic effects on inflammatory colitis.
Highlights
Spleen cells were treated with increasing amounts of DCPAB and HPAB after T cell receptor stimulation
To investigate the molecular mechanisms underlying IFN-γsuppression and inhibition of T helper 1 (Th1) cell differentiation by DCPAB and HPAB, we examined the effects DCPAB and HPAB on T-box containing protein expressed in T cells (T-bet) that is an essential Th1-specific transcription factor for inducing IFN-γgene transcription[21,22]
We examined whether DCPAB or HPAB affected the transcriptional activity of T-bet on IFN-γgene promoter
Summary
Numerous studies have attempted to develop therapeutic Ab drugs for the suppression of inflammatory cytokines[8], including anti-TNF-αdrugs (adalimumab, certolizumab pegol, etanercept, onercept and golimumab); an anti-CD20 Ab drug (rituximab); T-cell inhibitors (abatacept); and anti-α4 integrins (natalizumab and vedolizumab). These monoclonal Ab drugs show significant efficacy in the induction of remission and maintenance of IBD, but cause adverse effects and are not tolerated well. Whether benzoxazole derivatives modulate inflammatory cytokine production and have therapeutic effects in inflammatory bowel diseases require clarification
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