Naringenin is an inhibitor of T cell effector functions

Authors: NIU, XINLI - Henan University; WU, CHUNFANG - Henan University; LI, MENGYUE - Henan University; ZHAO, QING - Henan University; MEYDANI, SIMIN - Jean Mayer Human Nutrition Research Center On Aging At Tufts University; WANG, JUNPENG - Henan University; WU, DAYONG - Jean Mayer Human Nutrition Research Center On Aging At Tufts University

Submitted to: Journal of Nutritional Biochemistry
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 4/17/2018
Publication Date: 4/25/2018
Citation: Niu, X., Wu, C., Li, M., Zhao, Q., Meydani, S.N., Wang, J., Wu, D. 2018. Naringenin is an inhibitor of T cell effector functions. Journal of Nutritional Biochemistry. 58:71-79. https://doi.org/10.1016/j.jnutbio.2018.04.008.
DOI: https://doi.org/10.1016/j.jnutbio.2018.04.008

Interpretive Summary: In our previous study we found that dietary supplementation with naringenin, a flavonoid found most abundant in citrus fruits, reduced experimental autoimmune encephalomyelitis (EAE), a rodent model for human multiple sclerosis. This effect was associated with regulatory effect of naringenin on autoantigen-induced immuno-pathological changes in T cells. However, it is not known whether naringenin's effect on T cells is antigen-specific or a general character, and also what are the working mechanisms under this effect of naringenin. Our results showed that naringenin had direct inhibitory effect on T cell functions induced by a general or a specific stimulation. This effect can be explained by the observed modulating effect of naringenin on appropriate signaling processes involved in T cell activation and expansion. These results provided more in depth information for understanding the immuno-modulating properties of naringenin. Our results expanded our understanding for naringenin's working mechanisms in T cell-mediated immune disorders and the information obtained may help develop more specific dietary strategies in preventing and mitigating T cell-mediated autoimmune diseases.

Technical Abstract: Selective inhibition of T cells has been implied to prevent and/or treat autoimmune and inflammatory diseases. Some food compounds that have such immune-modulating functions may serve as nutritional approach to this purpose. In this study we chose naringenin, a citrus fruits-derived compound with anti-inflammatory property, to test this possibility. In this in vitro study, we stimulated mouse T cells with anti-CD3/CD28 (polyclonal TCR activation) or autoantigen MOG35-55 in the presence of naringenin. We found that naringenin does-dependently suppressed anti-CD3/CD28 and MOG35-55-induced T cell proliferation, production of T cell cytokines IFN-delta, IL-17, IL-6, and TNF-a. We further showed that inhibited T cell proliferation was associated with T cell cycle arrest at G0/G1 phase, which was in turn related to delayed degradation of the cyclin-dependent kinase inhibitor p27kip1 and the down-regulation of retinoblastoma protein phosphorylation in activated T cells. Finally, it was revealed that all these T cell-suppressive effects might be related to naringenin's interference with IL-2/IL-2R-mediated signaling pathway and STAT5 phosphorylation in activated T cells. Our results confirmed T cell-suppressive activity of naringenin previously reported by us and others, but for the first time it was shown that the working mechanism may involve its ability to modulate cell cycle progression, cell cycle-related proteins, and IL-2/IL-2R signaling pathway. Together these results further support proposed potential of naringenin being a preventive/therapeutic agent in T-cell mediated autoimmune inflammatory disorders.