AUTHOR=Nandan Amrita , Sharma Vishwas , Banerjee Prodyot , Sadasivam Kannan , Venkatesan Subramanian , Prasher Bhavana 

TITLE=Deciphering the mechanism of Tinospora cordifolia extract on Th17 cells through in-depth transcriptomic profiling and in silico analysis

JOURNAL=Frontiers in Pharmacology

VOLUME=13

YEAR=2023

URL=https://www.frontiersin.org/journals/pharmacology/articles/10.3389/fphar.2022.1056677

DOI=10.3389/fphar.2022.1056677

ISSN=1663-9812

ABSTRACT=<p>Naive CD4<sup>+</sup> T cells differentiate into effector (Th1, Th2, Th17) cells and immunosuppressive (Treg) cells upon antigenic stimulation in the presence of a specific cytokine milieu. The T cell <italic>in vitro</italic> culture system provides a very efficient model to study compounds’ therapeutic activity and mechanism of action. <italic>Tinospora cordifolia</italic> (Willd.) Hook.f. &amp; Thomson (Family. Menispermaceae) is one of the widely used drugs in <italic>Ayurveda</italic> (ancient Indian system of medicine) for various ailments such as inflammatory conditions, autoimmune disorders, and cancer as well as for promoting general health. <italic>In vitro</italic> and <italic>in vivo</italic> studies on immune cells comprising dendritic cells, macrophages, and B cells suggest its immune-modulating abilities. However, to date, the effect of <italic>T. cordifolia</italic> on individual purified and polarized T cell subsets has not been studied. Studying drug effects on T cell subsets is needed to understand their immunomodulatory mechanism and to develop treatments for diseases linked with T cell abnormalities. In this study, we examined the immunomodulatory activity of <italic>T. cordifolia</italic> on primary CD4<sup>+</sup> T cells, i.e., Th1, Th17, and iTreg cells. An aqueous extract of <italic>T. cordifolia</italic> was non-cytotoxic at concentrations below 1500 µg/ml and moderately inhibited the proliferation of naive CD4<sup>+</sup> T cells stimulated with anti-CD3ε and anti-CD28 for 96 h. <italic>T. cordifolia</italic> treatment of naive CD4<sup>+</sup> T cells differentiated under Th17-polarizing conditions exhibited reduced frequency of IL-17 producing cells with inhibition of differentiation and proliferation. For the first time, in-depth genome-wide expression profiling of <italic>T. cordifolia</italic> treated naive CD4<sup>+</sup> T cells, polarized to Th17 cells, suggests the broad-spectrum activity of <italic>T. cordifolia</italic>. It shows inhibition of the cytokine-receptor signaling pathway, majorly <italic>via</italic> the JAK-STAT signaling pathway, subsequently causing inhibition of Th17 cell differentiation, proliferation, and effector function. Additionally, the molecular docking studies of the 69 metabolites of <italic>T. cordifolia</italic> further substantiate the inhibitory activity of <italic>T. cordifolia via</italic> the cytokine-receptor signaling pathway. Furthermore, <italic>in vitro</italic> polarized Th1 and iTreg cells treated with <italic>T. cordifolia</italic> extract also showed reduced IFN-γ production and FoxP3 expression, respectively. This study provides insight into the plausible mechanism/s of anti-inflammatory activity of <italic>T. cordifolia</italic> involving T cells, mainly effective in Th17-associated autoimmune and inflammatory diseases.</p>