Piperlongumine Acts as an Immunosuppressant by Exerting Prooxidative Effects in Human T Cells Resulting in Diminished TH17 but Enhanced Treg Differentiation

Abstract

Piperlongumine (PL), a natural small molecule derived from the Piper longum Linn plant, has received growing interest as a prooxidative drug with promising anticancer properties. Yet, the influence of PL on primary human T cells remained elusive. Knowledge of this is of crucial importance, however, since T cells in particular play a critical role in tumor control. Therefore, we investigated the effects of PL on the survival and function of primary human peripheral blood T cells (PBTs). While PL was not cytotoxic to PBTs, it interfered with several stages of T cell activation as it inhibited T cell/APC immune synapse formation, co-stimulation-induced upregulation of CD69 and CD25, T cell proliferation and the secretion of proinflammatory cytokines. PL-induced immune suppression was prevented in the presence of thiol-containing antioxidants. In line with this finding, PL increased the levels of intracellular reactive oxygen species and decreased glutathione in PBTs. Diminished intracellular glutathione was accompanied by a decrease in S-glutathionylation on actin suggesting a global alteration of the antioxidant response. Gene expression analysis demonstrated that T H 17-related genes were predominantly inhibited by PL. Consistently, the polarization of primary human naïve CD4 + T cells into T H 17 subsets was significantly diminished while differentiation into T reg cells was substantially increased upon PL treatment. This opposed consequence for T H 17 and T reg cells was again abolished by thiol-containing antioxidants. Taken together, PL may act as a promising agent for therapeutic immunosuppression by exerting prooxidative effects in human T cells resulting in a diminished T H 17 but enhanced T reg cell differentiation.

Cholesterol suppresses human iTreg differentiation and nTreg function through mitochondria-related mechanisms

“…We speculate that mtROS and mtROS-induced HIF-1a may have opposite effects in iTreg differentiation, and the final outcome depends on which of the two plays a stronger role; the nature of the initial stimulus may be crucial in this process. For instance, Liang et al showed that the natural small molecule piperlongumine enhanced iTreg differentiation by exerting prooxidative effects; however, it also strongly inhibited the expression of HIF-1α [ 39 ]. In contrast, our data showed that cholesterol notably increased HIF-1α, which may offset the promotive effect of mtROS in iTreg differentiation.…”

Studi In Silico Potensi Piperine, Piperlongumine, dan Thymoquinone Sebagai Obat Alzheimer

“…Pada umumnya PIP telah banyak dimanfaatkan sebagai bioenhancer untuk meningkatkan bioavailabilitas obat yang dikombinasikan dengannya (7). Begitu pula dengan PL yang secara tradisional telah dimanfaatkan dalam pengobatan penyakit pencernaan, saluran pernafasan, dan menular seperti malaria (8). Secara tradisional TQ telah dimanfaatkan untuk mengobati banyak penyakit, misalnya asma, hipertensi, diabetes, peradangan, batuk, dan lain-lain dalam berbagai bentuk.…”

Resveratrol as an Adjunctive Therapy for Excessive Oxidative Stress in Aging COVID-19 Patients

“…Because TGF-β is a potent immunosuppressant affecting T lymphocytes, the release of ROS-mediated TGF-β can also contribute to the depletion of lymphocytes in COVID-19. Finally, maintaining T cells in a pro-oxidative state was shown to promote the development of Treg lymphocytes [ 114 ]. This relative increase in Tregs can also affect the ability of T cells to defend against a SARS-CoV-2 infection [ 102 ].…”