Epigallocatechin-3 Gallate Inhibits STAT-1/JAK2/IRF-1/HLA-DR/HLA-B and Reduces CD8 MKG2D Lymphocytes of Alopecia Areata Patients

Abstract

Background: Alopecia areata (AA) is associated with Interferon- γ (IFN-γ) mediated T-lymphocyte dysfunction and increased circulating Interleukine-17 (IL-17) levels. Epigallocatechin-3-gallate (EGCG) specifically inhibits IFN-γ pathways and unlike Janus Kinase 1 and 2 (JAK1/JAK2) inhibitors (tofacitinib, ruxolitinib), EGCG is safer, more cost-effective, and is a topically active agent. Our objective is to test the mode of action of EGCG in vitro and ex vivo using HaCat, Jurkat cell lines, and peripheral blood mononuclear cells (PBMCs) of AA patients and healthy controls (HCs), respectively. Methods: distribution of T helper cells (Th1, Th17), and cytotoxic cells (CD8) in PBMCs isolated from 30 AA patients and 30 HCs was investigated by flowcytomterty. In vitro treatment of HaCat and Jurkat cells with 40 μm EGCG for 48 h was performed to measure the level of phosphorylation of signal transducer and activator of transcription protein STAT1, and replicated in ex vivo model using PBMCs of AA patients. Results: Interestingly, 40 μm EGCG is capable of completely inhibiting phosphorylation of STAT1 after 48 h in HaCat and Jurkat cells and ex vivo in PBMCs of AA patients. Based on QPCR data, the action of EGCG on p-STAT1 seems to be mediated via downregulation of the expression of JAK2 but not JAK1 leading to the inhibition of human leukocyte antigens (HLA-DR and HLA-B) expression probably via IRF-1. On the other hand, AA patients have significantly increased levels of Th1, Th17, and CD8 cells and the production of IFN-γ and IL-17 by PBMCs in AA patients was significantly higher compared to HC; p = 0.008 and p = 0.006, respectively. Total numbers of CD8+ cells were not significantly different between treated and untreated samples. However, CD8+ cells with positive Natural killer group 2 member D (NKG2D) transmembrane receptor (CD8+ NKG2D+ subset) was significantly reduced when PBMCs were treated with 20 μm EGCG for 48 h. Conclusion: These results suggest that EGCG has a synergistic action that inhibits expression of HLA-DR and HLA-B molecules via the IFN-γ pathway to maintain immune privilege in HF; also it reduces CD8+ NKG2D+ subset.

Epigallocatechin‐3‐gallate exhibits anti‐inflammatory effects in a human interface dermatitis model—implications for therapy

“…Epigallocatechin-3-gallate has previously been investigated in various inflammatory dermatoses. [19][20][21][22][23]26,28 Green tea consumption has even been proposed as an alternative approach to managing oral LP. 36 The plasma concentration of EGCG detected upon intake of green tea extraction in 350 mL water, 37 however, is far from the concentration needed to achieve antiinflammatory effects.…”

“…19 Furthermore, EGCG alleviates psoriasiform [20][21][22] as well as atopic dermatitis-like lesions induced in mice. 23 Particularly, EGCG interferes with different mediators of immune responses activated in ID, including inhibition of nucleic acid sensing pathways 24,25 and Janus Kinase-Signal Transducer And Activator Of Transcription (JAK-STAT) pathways, [26][27][28] whose importance has been underlined in LP 29,30 and other autoimmune skin diseases featuring ID. [31][32][33] In the present study, we investigate the anti-inflammatory effectiveness of EGCG in the human in vitro model established by our working group and thus evaluate it as an innovative topically applicable therapeutic for patients suffering from LP and other autoimmune skin diseases featuring ID.…”

STAT1: A novel candidate biomarker and potential therapeutic target of the recurrent aphthous stomatitis

“…Finally, we have also confirmed that STAT1 protein is one of the potential therapeutic targets of RAS, and this target can be used to screen potential therapeutic compounds. Finally, genistein, daidzein, kaempferol, resveratrol, rosmarinic acid, triptolide, quercetin and (-)-epigallocatechin-3gallate were selceted from the TCMSP databse, and both of them is the STAT-1 inhibitor [48][49][50][51][52]. Interestingly, some of those ingredients, such as rosmarinic acid, quercetin, (-)-Epigallocatechin-3gallate, resveratrol, etc., have already been made into topical formulations for the treatment of oral ulcers, such as quercetin, (-)-Epigallocatechin-3-gallate, resveratrol [53][54][55].…”

Can plant‐derived phytochemicals provide symptom relief for hair loss? A critical review

“…Recently, the potential benefits of EGCG for treatment of the autoimmune hair loss condition, AA were reported, where the EGCG appeared to preserve immune privilege in an ex vivo assay, by inhibiting gamma interferon (IFN‐γ) pathways, . Blood samples from female patients with active hair loss and diagnosed AA were compared with age‐matched healthy controls.…”

“…Inflammatory T cells and intracellular cytokines (CD4, IFN‐γ, IL‐17) in AA patients' samples were increased in comparison to controls, thus confirming their role in the pathogenesis. Both patient PBLs and HKC (HaCat) were incubated with IFN‐γ, and treated with 40 µM EGCG, which specifically inhibited JAK2 expression, thus blocking the IFN‐γ pathway known to reduce the immune privilege of the HF .…”