Related Experiment Video
Updated: Sep 4, 2025
Scaled-Up Preparation of an Intermediate of Upatinib, ACT051-3
Published on: April 7, 2023
Effect of baricitinib in regulating programmed death 1 and ligand programmed cell death ligand 1 through JAK/STAT
H B Deepak1, Sabina Evan Prince2, Pratima Deshpande3
1Department of Biomedical Sciences, School of Biosciences and Technology, VIT, Vellore, Tamil Nadu; Department of Biology, Jubilant Biosys Ltd., Bengaluru, Karnataka, India.
Objectives:
Psoriasis is a chronic infectious skin disease triggered by an autoimmune process involving T-cell-mediated hyper-proliferation of keratinocytes. The objective of this study is to assess the modulation of programmed death 1 (PD-1) and its ligand programmed cell death ligand 1 (PD-L1) through JAK/STAT pathway during the development of a psoriasis-like disease by both in vitro and in vivo model. Baricitinib, a known inhibitor of JAK1 and JAK2, was used to study the impact on PD-1 and PD-L1.
Materials And Methods:
Human peripheral blood mononuclear cells (PBMC) were stimulated with either anti-CD3/CD28 or PMA/Ionomycin, to modulate level of PD-1 and PD-L1 under psoriasis-like condition. Interferon-gamma (IFNγ) was used to treat HaCaT cells to mimic the diseased keratinocytes found in Psoriatic patients. Psoriasis was induced with Imiquimod (IMQ) in animal model to study the cross-talk between different cell types and pathways.
Results:
Expression levels of PD-1 and PD-L1 in PBMC, and secretion of cytokines, namely tumor necrosis factor-α (TNFα), IFNγ, interleukin (IL)-6, and IL-1 β, were down-regulated on treatment with baricitinib. Further, in IFNγ-treated HaCaT cells (keratinocytes) mRNA levels of KRT-17 and PD-L1 were up-regulated.). Interestingly, in IFNγ-treated HaCat cells baricitinib decreased the levels of inflammatory cytokines such as IL-1 β, IL-6, and TNFα along with KRT-17 and PD-L1. On IFNγ-treatment. Data from both PBMC and HaCaT suggest an anti-inflammatory role for this compound. Accordingly, baricitinib was able to alleviate disease symptom in IMQ induce mice model of psoriasis. As a consequence of baricitinib treatment down-regulation of p-STAT3, PD- and PD-L1 expression levels were observed.
Conclusion:
This study demonstrates a crosstalk between JAK/STAT and PD-1/PD-L1 pathways. It also demonstrates that cytokines such as IFNγ and IL-17 are down-regulated by baricitinib. We believe decreased expressions of PD-1 and PD-L1 may be a consequence of baricitinib-induced down-regulation of IFNγ and IL-17. More importantly, our data from the acute model of psoriasis indicates that PD-L1 behaves as a T-cell-associated T-cell-associated surrogate activation marker rather than immunosuppressive marker in early phase of psoriasis. Therefore it does not exhibit a causal relationship to disease.
Insights
Baricitinib treatment down-regulated programmed cell death 1 (PD-1) and its ligand (PD-L1) in a psoriasis model by inhibiting the JAK/STAT pathway. This suggests baricitinib has anti-inflammatory effects and PD-L1 may act as a surrogate activation marker in early psoriasis.
Area of Science:
- Immunology
- Dermatology
- Pharmacology
Background:
- Psoriasis is a chronic autoimmune skin disease characterized by keratinocyte hyper-proliferation.
- The programmed death 1 (PD-1) and programmed cell death ligand 1 (PD-L1) pathway plays a role in immune regulation.
- The Janus kinase/signal transducer and activator of transcription (JAK/STAT) pathway is implicated in inflammatory responses.
Purpose of the Study:
- To investigate the modulation of PD-1 and PD-L1 via the JAK/STAT pathway in a psoriasis-like disease model.
- To assess the therapeutic potential of baricitinib, a JAK1/JAK2 inhibitor, on PD-1 and PD-L1 expression.
Main Methods:
- In vitro studies using human peripheral blood mononuclear cells (PBMC) and HaCaT keratinocytes stimulated to mimic psoriasis.
- In vivo studies using an imiquimod (IMQ)-induced psoriasis-like mouse model.
- Treatment with baricitinib to evaluate its effects on PD-1, PD-L1, cytokine levels, and JAK/STAT pathway activation.
Main Results:
- Baricitinib treatment down-regulated PD-1, PD-L1, and inflammatory cytokines (TNFα, IFNγ, IL-6, IL-1β) in PBMC and HaCaT cells.
- Baricitinib reduced KRT-17 and PD-L1 mRNA levels in IFNγ-treated HaCaT cells.
- Baricitinib alleviated psoriasis symptoms in the IMQ-induced mouse model, accompanied by decreased p-STAT3, PD-1, and PD-L1 expression.
Conclusions:
- A crosstalk exists between the JAK/STAT and PD-1/PD-L1 pathways in psoriasis development.
- Baricitinib exhibits anti-inflammatory effects by down-regulating cytokines like IFNγ and IL-17.
- PD-L1 may function as a surrogate T-cell activation marker rather than an immunosuppressive marker in the early stages of psoriasis.
More Related Videos
08:15Author Spotlight: Network Pharmacology and Molecular Docking to Decipher the Action of Jiawei Shengjiang San Against Diabetic Kidney Disease
Published on: May 10, 2024
08:49Identification of Mediators of T-cell Receptor Signaling via the Screening of Chemical Inhibitor Libraries
Published on: January 22, 2019
Related Concept Videos
01:20The JAK-STAT Signaling Pathway
01:22PI3K/mTOR/AKT Signaling Pathway
01:31The Intrinsic Apoptotic Pathway
01:16TGF - β Signaling Pathway
01:22Amplifying Signals via Enzymatic Cascade
02:26NF-κB-dependent Signaling Pathway
NF-κB-dependent Signaling Mechanism
The...