TNF increases Tyrosine Hydroxylase expression in human monocytes

Gopinath, A.; Francis, M.; Badov, M.; Shaw, G.; Collins, A.; Miller, D. R.; Hansen, C.; Mackie, P. M.; Tansey, M. G.; Dagra, A.; Madorsky, I.; Ramirez-Zamora, A.; Okun, M.; Streit, W. J.; Khoshbouei, H.

doi:10.1101/2021.04.13.439627

bioRxiv · 10.1101/2021.04.13.439627

TNF increases Tyrosine Hydroxylase expression in human monocytes

Gopinath, A.·Francis, M.·Badov, M.·Shaw, G.·Collins, A.·Miller, D. R.·Hansen, C.·Mackie, P. M.·Tansey, M. G.·Dagra, A.·Madorsky, I.·Ramirez-Zamora, A.·Okun, M.·Streit, W. J.·Khoshbouei, H.

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Abstract

Most, if not all, peripheral immune cells in humans and animals express tyrosine hydroxylase (TH), the rate limiting enzyme in catecholamine synthesis. Since TH is typically studied in the context of brain catecholamine signaling, little is known about changes in TH production and function in peripheral immune cells. This knowledge gap is due, in part, to the lack of an adequately sensitive assay to measure TH in immune cells expressing lower TH levels compared to other TH expressing cells. Here, we report the development of a highly sensitive and reproducible Bio-ELISA to quantify picogram levels of TH in multiple model systems. We have applied this assay to monocytes isolated from blood of persons with Parkinsons disease (PD) and to age-matched, healthy controls. Our study unexpectedly revealed that PD patients monocytes express significantly higher levels of TH protein in peripheral monocytes relative to healthy controls. Tumor necrosis factor (TNF{delta}), a pro-inflammatory cytokine, has also been shown to be increased in the brains and peripheral circulation in human PD, as well as in animal models of PD. Therefore, we investigated a possible connection between higher levels of TH protein and the known increase in circulating TNF{delta} in PD. Monocytes isolated from healthy donors were treated with TNF{delta} or with TNF{delta} in the presence of an inhibitor. Tissue plasminogen activator (TPA) was used as a positive control. We observed that TNF{delta} stimulation increased both the number of TH+ monocytes and the quantity of TH per monocyte, without increasing the total numbers of monocytes. These results revealed that TNF{delta} could potentially modify monocytic TH production and serve a regulatory role in peripheral immune function. The development and application of a highly sensitive assay to quantify TH in both human and animal cells will provide a novel tool for further investigating possible PD immune regulatory pathways between brain and periphery.

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Gopinath, A., Francis, M., Badov, M., Shaw, G., Collins, A., Miller, D. R., Hansen, C., Mackie, P. M., Tansey, M. G., Dagra, A., Madorsky, I., Ramirez-Zamora, A., Okun, M., Streit, W. J., Khoshbouei, H.. 2021-04-14. TNF increases Tyrosine Hydroxylase expression in human monocytes. https://doi.org/10.1101/2021.04.13.439627

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