Abstract
The appropriate regulation of T cell activity under inflammatory conditions is crucial for maintaining immune homeostasis. Salinosporamide A discovered as a self-resistance product from the marine bacterium Salinospora tropica, has been used as a potent proteasome inhibitor (PI). Although PIs have been developed as novel therapeutics for autoimmune diseases, due to their immunosuppressive effect, whether salinosporamide A inhibits T cell activation remains unknown. The current study finds that salinosporamide A is not cytotoxic, but controls T cell proliferation. Results from our cell cycle arrest analysis revealed that salinosporamide A leads to cell cycle arrest and regulates the expression of cyclin-dependent kinases. Under activated conditions, salinosporamide A abrogated T cell activation by T cell receptor-mediated stimulation, in which the production of cytokines was inhibited by pretreatment with salinosporamide A. Furthermore, we demonstrated that the regulation of T cell activation by salinosporamide A is mediated by suppressing the MAPK pathway. Therefore, our results suggest that salinosporamide A effectively suppresses T cell activation through regulating T cell proliferation and the cell cycle and provides great insight into the development of novel therapeutics for autoimmune diseases or graft-versus-host disease.
Highlights
During the immune response, the proper regulation of T cells is pivotal for maintaining immunological homeostasis, because T cells link humoral immunity to adaptive immunity [1].several events related to T cell activation, including antigenic priming by antigen-presenting cells, activation, and differentiation into effector T cells, should be accurately controlled
Despite the fact that salinosporamide A is cytotoxic at concentrations of 20 nM and 40 nM, which has Despite the fact that salinosporamide A is cytotoxic at concentrations of 20 nM and 40 nM, which been reported as the IC50 value of salinosporamide A, we evaluated whether salinosporamide A was has been reported as the IC50 value of salinosporamide A, we evaluated whether salinosporamide A
We demonstrated that salinosporamide A derived from marine life suppresses
Summary
The proper regulation of T cells is pivotal for maintaining immunological homeostasis, because T cells link humoral immunity to adaptive immunity [1]. Reduced T cell growth rates have been observed in the presence of neutralizing antibodies against IL-2, and T cells that are engagement or antigenic mitogen activation have shown proliferation treatment with IL-2 [9,10]. Several immunosuppressive reagents inhibit T cell proliferation in the stimulation lead to cell cycle arrest [11,12]. Tcell reagents have commercially developed, is known about whether molecules derived activation through proliferation pathways or cell cycle arrest. Salinosporamide A efficiently suppressed cell proliferation and promoted cell cycle arrest, in a doseThese inhibitory mechanisms result in the inhibition of. T cellinactivity and the MAPK signaling dependent manner These inhibitory mechanisms result the inhibition of T cell activitypathway, and the following stimulation by anti-CD3 and CD28 antibodies.
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