• Title/Summary/Keyword: PD-1

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PD-1 Expression in LPS-Induced Raw264.7 Cells Is Regulated via Co-activation of Transcription Factor NF-κB and IRF-1 (Lipopolysaccharide 유도된 Raw264.7 세포주에서 전사조절인자 NF-κB와 IRF-1의 공동작용에 의해 조절되는 PD-1 발현연구)

  • Choi, Eun-Kyoung;Lee, Soo-Woon;Lee, Soo-Woong
    • Korean Journal of Microbiology
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    • v.49 no.4
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    • pp.301-308
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    • 2013
  • Programmed Death-1 (PD-1) is one of the important immune-inhibitory molecules which was expressed in T cells, B cells, NKT cells, and macrophages activated by various immune activating factors. Lipopolysaccharide (LPS), the major component of the outer membrane of Gram-negative bacteria, is one of the crucial immunogens for PD-1 expression. However, there are only a few reports on the expression mechanisms of PD-1 in innate immune cells. In this study, we investigate the expression mechanisms of PD-1 in LPS-stimulated Raw264.7 cell lines by RT-PCR, Western Blot, flow cytometry as well as ChIP assay and co-immunoprecipitation. When Raw264.7 cells were stimulated with LPS, PD-1 expression was greatly up-regulated via PI3K and p38 signaling. Primary macrophages isolated from LPS-injected mice were also shown the increased expression of PD-1. In promoter assay, NF-${\kappa}B$ and IRF-1 binding regions in mouse PD-1 promoter are important for PD-1 expression. We also found that the co-activation of NF-${\kappa}B$ and IRF-1 is indispensable for the maximum PD-1 expression. These results indicate that the modulation of PD-1 expressed in innate immune cells could be a crucial for the disease therapy such as LPS-induced mouse sepsis model.

PD-1 deficiency protects experimental colitis via alteration of gut microbiota

  • Park, Seong Jeong;Kim, Ji-Hae;Song, Mi-Young;Sung, Young Chul;Lee, Seung-Woo;Park, Yunji
    • BMB Reports
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    • v.50 no.11
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    • pp.578-583
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    • 2017
  • Programmed cell death-1 (PD-1) is a coinhibitory molecule and plays a pivotal role in immune regulation. Here, we demonstrate a role for PD-1 in pathogenesis of inflammatory bowel disease (IBD). Wild-type (WT) mice had severe wasting disease during experimentally induced colitis, while mice deficient for PD-1 ($PD-1^{-/-}$) did not develop colon inflammation. Interestingly, $PD-1^{-/-}$ mice cohoused with WT mice became susceptible to colitis, suggesting that resistance of $PD-1^{-/-}$ mice to colitis is dependent on their gut microbiota. 16S rRNA gene-pyrosequencing analysis showed that $PD-1^{-/-}$ mice had altered composition of gut microbiota with significant reduction in Rikenellaceae family. These altered colon bacteria of $PD-1^{-/-}$ mice induced less amount of inflammatory mediators from colon epithelial cells, including interleukin (IL)-6, and inflammatory chemokines. Taken together, our study indicates that PD-1 expression is involved in the resistance to experimental colitis through altered bacterial communities of colon.

Analysis of the Expression and Regulation of PD-1 Protein on the Surface of Myeloid-Derived Suppressor Cells (MDSCs)

  • Nam, Sorim;Lee, Aram;Lim, Jihyun;Lim, Jong-Seok
    • Biomolecules & Therapeutics
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    • v.27 no.1
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    • pp.63-70
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    • 2019
  • Myeloid-derived suppressor cells (MDSCs) that are able to suppress T cell function are a heterogeneous cell population frequently observed in cancer, infection, and autoimmune disease. Immune checkpoint molecules, such as programmed death 1 (PD-1) expressed on T cells and its ligand (PD-L1) expressed on tumor cells or antigen-presenting cells, have received extensive attention in the past decade due to the dramatic effects of their inhibitors in patients with various types of cancer. In the present study, we investigated the expression of PD-1 on MDSCs in bone marrow, spleen, and tumor tissue derived from breast tumor-bearing mice. Our studies demonstrate that PD-1 expression is markedly increased in tumor-infiltrating MDSCs compared to expression in bone marrow and spleens and that it can be induced by LPS that is able to mediate $NF-{\kappa}B$ signaling. Moreover, expression of PD-L1 and CD80 on $PD-1^+$ MDSCs was higher than on $PD-1^-$ MDSCs and proliferation of MDSCs in a tumor microenvironment was more strongly induced in $PD-1^+$ MDSCs than in $PD-1^-$ MDSCs. Although we could not characterize the inducer of PD-1 expression derived from cancer cells, our findings indicate that the study on the mechanism of PD-1 induction in MDSCs is important and necessary for the control of MDSC activity; our results suggest that $PD-1^+$ MDSCs in a tumor microenvironment may induce tumor development and relapse through the modulation of their proliferation and suppressive molecules.

A Case of Aggravation of Thyroid Goiter after Treatment with PD-1 Inhibitor for Breast Cancer in Patients with Underlying Hashimoto's Thyroiditis (기저 하시모토 갑상선염이 있던 유방암 환자에서 PD-1 억제제 투약 후 악화된 갑상선 종대의 증례)

  • Kim, Hana;Kim, Min Joo;Song, Young Shin;Cho, Sun Wook
    • International journal of thyroidology
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    • v.11 no.2
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    • pp.172-175
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    • 2018
  • Anti-programmed cell death-1 (PD-1) humanized monoclonal antibody inhibits PD-1 activity by binding to the PD-1 receptor on T-cells and blocking PD-1 ligands and induces immune tolerance of cancer cells. It has been widely used for various kinds of cancer treatment. However, many immune-related adverse events (irAEs) have been reported because it modulates our immune system. In this case study, we reported a case of 42-year-old woman with Hashimoto's thyroiditis who showed rapid aggravation of thyroid goiter and acute hyperventilation syndrome after treatment with PD-1 inhibitor as a neoadjuvant chemotherapy for breast cancer.

Neuroprotective Effect of PD-1 Extract in MPTP-lesioned Mouse Model of Parkinson's Disease (1-methyl-4-phenyl-1,2,3,6-tetrahydrophridine으로 유도된 파킨슨병 쥐에서의 도파민 신경세포 손상에 대한 PD-1 처방의 보호 효과)

  • Lee, Jung-Wook;Jung, Hye-Mi;Seo, Un-Kyo
    • The Journal of Korean Medicine
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    • v.30 no.4
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    • pp.79-92
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    • 2009
  • Objectives: The aim of the present study was to explore the neuroprotective effect and the possible mechanism of the PD-1 extracts on 1-methyl-4-phenyl-1,2,3,6-tetrahydrophridine (MPTP)-lesioned C57BL/6 mouse model of Parkinson's disease (PD). Methods: The mice were supplemented (or not) with 50 or 100 mg/kg/day of PD-1 for 2 weeks, after which MPTP was injected intraperitoneally. We observed that daily administration of PD-1 prevented MPTP-induced depletion of striatal DA, and maintained striatal and nigral tyrosine hydroxylase (TH) protein levels. Results: Our results demonstrated that mice treated with PD-1 prior to MPTP administration showed more abundant TH-immunopositive (TH-ir) fibers and neurons than mice given only MPTP, indicating that PD-1 protects dopaminergic striatal fibers and nigral neurons from MPTP insults. Possible neuroprotective effect of PD-1 was further studied by the detection of antiapoptotic protein (bcl-2) and proapoptotic protein (Bax). In this assay, MPTP elevated the Bax protein and decreased the bcl-2 protein, while these expressions were prevented by PD-1 pre-treatment. Conclusions: The present results suggest that PD-1 is able to protect dopaminergic neurons from MPTP-induced neuronal injury with anti-apoptotic activity being one of the possible mechanisms.

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Reconstructed Adeno-Associated Virus with the Extracellular Domain of Murine PD-1 Induces Antitumor Immunity

  • Elhag, Osama A.O.;Hu, Xiao-Jing;Wen-Ying, Zhang;Li, Xiong;Yuan, Yong-Ze;Deng, Ling-Feng;Liu, De-Li;Liu, Ying-Le;Hui, Geng
    • Asian Pacific Journal of Cancer Prevention
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    • v.13 no.8
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    • pp.4031-4036
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    • 2012
  • Background: The negative signaling provided by interactions of the co-inhibitory molecule, programmed death-1 (PD-1), and its ligands, B7-H1 (PD-L1) and B7-DC (PD-L2), is a critical mechanism contributing to tumor evasion; blockade of this pathway has been proven to enhance cytotoxic activity and mediate antitumor therapy. Here we evaluated the anti-tumor efficacy of AAV-mediated delivery of the extracellular domain of murine PD-1 (sPD-1) to a tumor site. Material and Methods: An rAAV vector was constructed in which the expression of sPD-1, a known negative regulator of TCR signals, is driven by human cytomegalovirus immediate early promoter (CMV-P), using a triple plasmid transfection system. Tumor-bearing mice were then treated with the AAV/sPD1 construct and expression of sPD-1 in tumor tissues was determined by semi quantitative RT-PCR, and tumor weights and cytotoxic activity of splenocytes were measured. Results: Analysis of tumor homogenates revealed sPD-1 mRNA to be significantly overexpressed in rAAV/sPD-1 treated mice as compared with control levels. Its use for local gene therapy at the inoculation site of H22 hepatoma cells could inhibit tumor growth, also enhancing lysis of tumor cells by lymphocytes stimulated specifically with an antigen. In addition, PD-1 was also found expressed on the surfaces of activated CD8+ T cells. Conclusion: This study confirmed that expression of the soluble extracellular domain of PD-1 molecule could reduce tumor microenvironment inhibitory effects on T cells and enhance cytotoxicity. This suggests that it might be a potential target for development of therapies to augment T-cell responses in patients with malignancies.

An engineered PD-1-based and MMP-2/9-oriented fusion protein exerts potent antitumor effects against melanoma

  • Wei, Mulan;Liu, Xujie;Cao, Chunyu;Yang, Jianlin;Lv, Yafeng;Huang, Jiaojiao;Wang, Yanlin;Qin, Ye
    • BMB Reports
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    • v.51 no.11
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    • pp.572-577
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    • 2018
  • Recent studies showed that the PD-1/PD-L1 checkpoint blockade is a dramatic therapy for melanoma by enhancing antitumor immune activity. Currently, major strategies for the PD-1/PD-L1 blockade have mainly focused on the use of antibodies and compounds. Seeking an alternative approach, others employ endogenous proteins as blocking agents. The extracellular domain of PD-1 (ePD1) includes the binding site with PD-L1. Accordingly, we constructed a PD-1-based recombinantly tailored fusion protein (dFv-ePD1) that consists of bivalent variable fragments (dFv) of an MMP-2/9-targeted antibody and ePD1. The melanoma-binding intensity and antitumor activity were also investigated. We found the intense and selective binding capability of the protein dFv-ePD1 to human melanoma specimens was confirmed by a tissue microarray. In addition, dFv-ePD1 significantly suppressed the migration and invasion of mouse melanoma B16-F1 cells, and displayed cytotoxicity to cancer cells in vitro. Notably, dFv-ePD1 significantly inhibited the growth of mouse melanoma B16-F1 tumor cells in mice and in vivo fluorescence imaging showed that dFv-ePD was gradually accumulated into the B16-F1 tumor. Also the B16-F1 tumor fluorescence intensity at the tumor site was stronger than that of dFv. This study indicates that the recombinant protein dFv-ePD1 has an intensive melanoma-binding capability and exerts potent therapeutic efficacy against melanoma. The novel format of the PD-L1-blocked agent may play an active role in antitumor immunotherapy.

Measles Viral Infection in PD-1 Gene Knockout Mice (PD-1 유전자 제거 마우스에서 홍역바이러스 감염)

  • Chun, Jin Kyong;Kim, Kyu Yeun;Hur, Ji Ae;Kang, Dong Won;Kim, Ki Hwan;Kim, Dong Soo
    • Pediatric Infection and Vaccine
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    • v.20 no.3
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    • pp.123-130
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    • 2013
  • Purpose: Subacute sclerosing panencephalitis (SSPE) is a neurodegerative disease due to persistent measles virus infection. We investigated the role of programmed death-1 (PD-1) molecule which is related with chronic viral infection in developing SSPE in mouse. Methods: We adopt the $PD-1^{-/-}$, $PD-1^{-/+}$, and wild type BALB/c 3 week old mice to make an animal model of SSPE by injecting measles virus (SSPE strain) intraventricularly. Three months after infusion of virus, the mice were sacrificed and examined if the typical pathologic lesions had been progressed. The sera were collected from each group of mice and the serum level of IL-21 was measured with ELISA kit. Results: The necrotic lesions on white matter and gliosis were found in focal areas in wild type BALB/c. The extent of lesion was smaller in heterotype BALB/c. Scanty lesions were found in $PD-1^{-/-}$ mice. The sera level of IL-21 was not elevated in all three groups. Conclusion: Our data suggest that the PD-1 molecule may play a role in persistent viral infection.

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Suppressive Effect of 4-Hydroxy-2-(4-Hydroxyphenethyl) Isoindoline-1,3-Dione on Ovalbumin-Induced Allergic Asthma

  • Huang, Jin;Su, Mingzhi;Lee, Bo-Kyung;Kim, Mee-Jeong;Jung, Jee H.;Im, Dong-Soon
    • Biomolecules & Therapeutics
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    • v.26 no.6
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    • pp.539-545
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    • 2018
  • 4-Hydroxy-2-(4-hydroxyphenethyl)isoindoline-1,3-dione (PD1) is a synthetic phthalimide derivative of a marine compound. PD1 has peroxisome proliferator-activated receptor (PPAR) ${\gamma}$ agonistic and anti-inflammatory effects. This study aimed to investigate the effect of PD1 on allergic asthma using rat basophilic leukemia (RBL)-2H3 mast cells and an ovalbumin (OVA)-induced asthma mouse model. In vitro, PD1 suppressed ${\beta}$-hexosaminidase activity in RBL-2H3 cells. In the OVA-induced allergic asthma mouse model, increased inflammatory cells and elevated Th2 and Th1 cytokine levels were observed in bronchoalveolar lavage fluid (BALF) and lung tissue. PD1 administration decreased the numbers of inflammatory cells, especially eosinophils, and reduced the mRNA and protein levels of the Th2 cytokines including interleukin (IL)-4 and IL-13, in BALF and lung tissue. The severity of inflammation and mucin secretion in the lungs of PD1-treated mice was also less. These findings indicate that PD1 could be a potential compound for anti-allergic therapy.

The Roles of Immune Regulatory Factors FoxP3, PD-1, and CTLA-4 in Chronic Viral Infection (만성 바이러스 감염에서 면역조절인자 FoxP3, PD-1 및 CTLA-4의 역할)

  • Cho, Hyosun
    • Korean Journal of Microbiology
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    • v.49 no.3
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    • pp.221-227
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    • 2013
  • Human immunodeficiency virus (HIV), hepatitis B virus (HBV), and hepatitis C virus (HCV) cause viral infections that lead to chronic diseases. When they invade human body, virus specific T cells play an important role in antiviral effector functions including killing virus-infected cells and helping B cells to produce specific antibodies against viral proteins. The antiviral activity of T cells is usually affected by immune-regulatory factors that express on surface of T cells. Recently, many researchers have investigated the relationship between effector functions of virus specific T cells and characteristics of immune regulatory factors (e.g., CD28, CD25, CD45RO, FoxP3, PD-1, CTLA-4). In particular, Immune inhibitory molecules such as forkhead box P3 (FoxP3), programmed death-1 (PD-1), and cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) are associated with T-cell dysfunction. They are shown to be up-regulated in chronic viral diseases such as hepatitis B, hepatitis C or human immunodeficiency virus infection. Therefore, the positive correlation between viral persistence and expression of immune regulatory factors (FoxP3, PD-1, and CTLA-4) has been suggested. In this review, the roles of immune regulatory factors FoxP3, PD-1, and CTLA-4 were discussed in chronic viral diseases such as HIV, HBV, or HCV.