Functional analysis of the transcription factor NFATc3 in the promotion of intestinal inflammation

Inflammatory bowel disease (IBD), which includes Crohn's disease (CD) and ulcerative colitis (UC), is a disease of the immune system caused by a variety of factors, including environmental factors, intestinal microbiota, over-immunisation and genetic susceptibility. Its incidence has been increasing over the past few decades, both in developing and developed countries. Previous studies have shown that abnormal regulation of T cells plays an important role in the auto-inflammatory process of IBD. At the same time, calcium (Ca2+) signaling has been found to be critical for T cell activation as a means of rapidly activating and integrating numerous signaling pathways that result in a wide range of changes in T cell gene expression and function. This understanding has led to the development of novel therapies for IBD, but due to multiple causative factors, IBD remains incurable. However, over the past few decades, different medications have been discovered that not only relieve symptoms but also prolong the period of remission between acute attacks. One of medication is immunosuppressant Cyclosporin A (CsA), which is a calcineurin inhibitor. In the beginning, it was widely used in transplantation and has greatly improved survival rates of patients after solid organ transplantation. Currently, CsA is mostly used in the acute clinical treatment of UC patients but not in CD patients. Unfortunately, CsA has serious side effects, which will severely limit its clinical application if used for a long time. Fortunately, further development of the new calcineurin inhibitor medication, voclosporin, has been accomplished. Voclosporin, which is derived from CsA. However, the structure of voclosporin has been changed in order to improve its effectiveness, metabolic stability and safety. Voclosporin has been used as an immunosuppressant medication for the treatment of colitis induced by DSS. Therefore, calcineruin inhibitors, CsA and voclosporin have been used to treat autoimmune diseases such as IBD. NFATc3 is a lymphocyte-specific transcription factor of NFATc family member that is calcium-regulated by the T-cell antigen receptor (TCR), which regulates the developmental transformation of the thymus and also mediates immune activation of mature peripheral T cells. The transcription factor NFATc3 was found to be particularly upregulated in IBD patients. The transcription factor NFATc3 also plays a key role in the pathogenesis of experimental colitis. Therefore, NFATc3 could be a potential target for new drugs. Here, it can be demonstrated that knockdown of NFATc3 leads to a decrease in the secretion of pro-inflammatory cytokines, thus reducing intestinal inflammation. In addition, CsA and Voclosporin were found to attenuate intestinal inflammation by inhibiting NFATc3 expression in experimental colitis models, which medicated by the hapten oxazolone. In conclusion, these results clearly indicate that, on the one hand, CsA and Voclosporin exert their protective effects by downregulating the function of NFATc3, and on the other hand, inhibition of NFATc3 by genetic approaches reduces experimental inflammation. Therefore, specific blocking of NFATc3 may be a promising target for future drug design, which not only improves the therapeutic efficacy of IBD, but also improves the quality of life of patients.