Parasites, Hosts and Diseases

"STAT6"

Original Article

Afatinib Reduces STAT6 Signaling of Host ARPE-19 Cells Infected with Toxoplasma gondii: Zhaoshou Yang, Hye-Jin Ahn, Young-Hoon Park, Ho-Woo Nam; Korean J Parasitol 2016;54(1):31-38.
Published online February 26, 2016; DOI: https://doi.org/10.3347/kjp.2016.54.1.31

Abstract
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Specific gene expressions of host cells by spontaneous STAT6 phosphorylation are major strategy for the survival of intracellular Toxoplasma gondii against parasiticidal events through STAT1 phosphorylation by infection provoked IFN-γ. We determined the effects of small molecules of tyrosine kinase inhibitors (TKIs) on the growth of T. gondii and on the relationship with STAT1 and STAT6 phosphorylation in ARPE-19 cells. We counted the number of T. gondii RH tachyzoites per parasitophorous vacuolar membrane (PVM) after treatment with TKIs at 12-hr intervals for 72 hr. The change of STAT6 phosphorylation was assessed via western blot and immunofluorescence assay. Among the tested TKIs, Afatinib (pan ErbB/EGFR inhibitor, 5 ?M) inhibited 98.0% of the growth of T. gondii, which was comparable to pyrimethamine (5 ?M) at 96.9% and followed by Erlotinib (ErbB1/EGFR inhibitor, 20 ?M) at 33.8% and Sunitinib (PDGFR or c-Kit inhibitor, 10 ?M) at 21.3%. In the early stage of the infection (2, 4, and 8 hr after T. gondii challenge), Afatinib inhibited the phosphorylation of STAT6 in western blot and immunofluorescence assay. Both JAK1 and JAK3, the upper hierarchical kinases of cytokine signaling, were strongly phosphorylated at 2 hr and then disappeared entirely after 4 hr. Some TKIs, especially the EGFR inhibitors, might play an important role in the inhibition of intracellular replication of T. gondii through the inhibition of the direct phosphorylation of STAT6 by T. gondii.

Citations

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Small molecule kinase inhibitor altiratinib inhibits brain cyst forming bradyzoites of Toxoplasma gondii
Yeong Hoon Kim, Hye-Jin Ahn, Hwa Sun Kim, Ho-Woo Nam
Journal of Microbiology.2025; 63(2): e2409001. CrossRef
iTRAQ-Based Phosphoproteomic Analysis Exposes Molecular Changes in the Small Intestinal Epithelia of Cats after Toxoplasma gondii Infection
Bintao Zhai, Yu-Meng Meng, Shi-Chen Xie, Jun-Jie Peng, Yang Liu, Yanhua Qiu, Lu Wang, Jiyu Zhang, Jun-Jun He
Animals.2023; 13(22): 3537. CrossRef
Secretome Analysis of Host Cells Infected with Toxoplasma gondii after Treatment of Human Epidermal Growth Factor Receptor 2/4 Inhibitors
Hye-Jung Kim, Hye-Jin Ahn, Hyeweon Kang, Jaehui Park, Seul gi Oh, Saehae Choi, Won-Kyu Lee, Ho-Woo Nam
The Korean Journal of Parasitology.2020; 58(3): 249. CrossRef
A Human Proteome Array Approach to Identifying Key Host Proteins Targeted by Toxoplasma Kinase ROP18
Zhaoshou Yang, Yongheng Hou, Taofang Hao, Hee-Sool Rho, Jun Wan, Yizhao Luan, Xin Gao, Jianping Yao, Aihua Pan, Zhi Xie, Jiang Qian, Wanqin Liao, Heng Zhu, Xingwang Zhou
Molecular & Cellular Proteomics.2017; 16(3): 469. CrossRef
Adverse Event Profile of Pyrimethamine-Based Therapy in Toxoplasmosis: A Systematic Review
Ruben R. Ben-Harari, Elizabeth Goodwin, Julio Casoy
Drugs in R&D.2017; 17(4): 523. CrossRef
Suppressors for Human Epidermal Growth Factor Receptor 2/4 (HER2/4): A New Family of Anti-Toxoplasmic Agents in ARPE-19 Cells
Yeong Hoon Kim, Lokraj Bhatt, Hye-Jin Ahn, Zhaoshou Yang, Won-Kyu Lee, Ho-Woo Nam
The Korean Journal of Parasitology.2017; 55(5): 491. CrossRef

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Brief Communication

STAT6 Expression and IL-13 Production in Association with Goblet Cell Hyperplasia and Worm Expulsion of Gymnophalloides seoi from C57BL/6 Mice: Jin-Joo Lee, Donghee Kim, Kyoung-Ho Pyo, Min-Ki Kim, Hyo-Jin Kim, Jong-Yil Chai, Eun-Hee Shin; Korean J Parasitol 2013;51(5):589-594.
Published online October 31, 2013; DOI: https://doi.org/10.3347/kjp.2013.51.5.589

Abstract
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In intestinal helminth infections, Th2 immune respones are generally associated with mucin secretion for worm expulsion from the host intestine. In particular, IL-4 and IL-13 are the important cytokines related with intestinal mucus production via STAT6 signalling in nematode infections. However, this perspective has never been studied in Gymnophalloides seoi infection. The present study aimed to observe the STAT6 signalling and cytokine responses in C57BL/6 mice, a mouse strain resistant to infection with this trematode. The results showed that worm expulsion occurred actively during days 1-2 post-infection (PI), when goblet cells began to proliferate in the small intestine. The STAT6 gene expression in the mouse spleen became remarkable from day 2 PI. Moreover, G. seoi infection induced a significant increase of IL-13 from day 4 PI in the spleen of infected mice. Our results suggested that goblet cell hyperplasia and worm expulsion in G. seoi-infected mice should be induced by STAT6 signalling, in which IL-13 may be involved as a dominant triggering cytokine.

Citations

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Immune Regulation of Goblet Cell and Mucus Functions in Health and Disease
Jenny K. Gustafsson, Gunnar C. Hansson
Annual Review of Immunology .2025; 43(1): 169. CrossRef
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Franziska Bayer, Olga Dremova, My Phung Khuu, Könül Mammadova, Giulia Pontarollo, Klytaimnistra Kiouptsi, Natalia Soshnikova, Helen Louise May-Simera, Kristina Endres, Christoph Reinhardt
Nutrients.2021; 13(7): 2198. CrossRef
Role of Goblet Cells in Intestinal Barrier and Mucosal Immunity
Songwei Yang, Min Yu
Journal of Inflammation Research.2021; Volume 14: 3171. CrossRef
The relationship between intestinal goblet cells and the immune response
Mingming Zhang, Chenchen Wu
Bioscience Reports.2020;[Epub] CrossRef
Developmental expression of STATs, nuclear factor-κB and inflammatory genes in the jejunum of piglets during weaning
Hongbo Yi, Denghu Jiang, Lin Zhang, Haitao Xiong, Feifei Han, Yizhen Wang
International Immunopharmacology.2016; 36: 199. CrossRef
Increased Intestinal Epithelial Cell Turnover and Intestinal Motility in Gymnophalloides seoi-Infected C57BL/6 Mice
Sang Hyub Lee, Bong-Kwang Jung, Jae-Hwan Park, Eun-Hee Shin, Jong-Yil Chai
The Korean Journal of Parasitology.2014; 52(3): 273. CrossRef

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Original Articles

Anti-Apoptotic Effects of SERPIN B3 and B4 via STAT6 Activation in Macrophages after Infection with Toxoplasma gondii: Kyoung Ju Song, Hye-Jin Ahn, Ho-Woo Nam; Korean J Parasitol 2012;50(1):1-6.
Published online March 6, 2012; DOI: https://doi.org/10.3347/kjp.2012.50.1.1

Abstract
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Toxoplasma gondii penetrates all kinds of nucleated eukaryotic cells but modulates host cells differently for its intracellular survival. In a previous study, we found out that serine protease inhibitors B3 and B4 (SERPIN B3/B4 because of their very high homology) were significantly induced in THP-1-derived macrophages infected with T. gondii through activation of STAT6. In this study, to evaluate the effects of the induced SERPIN B3/B4 on the apoptosis of T. gondii-infected THP-1 cells, we designed and tested various small interfering (si-) RNAs of SERPIN B3 or B4 in staurosporine-induced apoptosis of THP-1 cells. Anti-apoptotic characteristics of THP-1 cells after infection with T. gondii disappeared when SERPIN B3/B4 were knock-downed with gene specific si-RNAs transfected into THP-1 cells as detected by the cleaved caspase 3, poly-ADP ribose polymerase and DNA fragmentation. This anti-apoptotic effect was confirmed in SERPIN B3/B4 overexpressed HeLa cells. We also investigated whether inhibition of STAT6 affects the function of SERPIN B3/B4, and vice versa. Inhibition of SERPIN B3/B4 did not influence STAT6 expression but SERPIN B3/B4 expression was inhibited by STAT6 si-RNA transfection, which confirmed that SERPIN B3/B4 was induced under the control of STAT6 activation. These results suggest that T. gondii induces SERPIN B3/B4 expression via STAT6 activation to inhibit the apoptosis of infected THP-1 cells for longer survival of the intracellular parasites themselves.

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Modulation of STAT-1, STAT-3, and STAT-6 activities in THP-1 derived macrophages infected with two Trypanosoma cruzi strains
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Frontiers in Immunology.2022;[Epub] CrossRef
BEWO trophoblast cells and Toxoplasma gondii infection modulate cell death mechanisms in THP-1 monocyte cells by interference in the expression of death receptor and intracellular proteins
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Tissue and Cell.2021; 73: 101658. CrossRef
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RNA Biology.2020; 17(5): 731. CrossRef
Secretome Analysis of Host Cells Infected with Toxoplasma gondii after Treatment of Human Epidermal Growth Factor Receptor 2/4 Inhibitors
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The Korean Journal of Parasitology.2020; 58(3): 249. CrossRef
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IL-4 Independent Nuclear Translocalization of STAT6 in HeLa Cells by Entry of Toxoplasma gondii: Hye-Jin Ahn, Ji Yeon Kim, Ho-Woo Nam; Korean J Parasitol 2009;47(2):117-124.
Published online May 27, 2009; DOI: https://doi.org/10.3347/kjp.2009.47.2.117

Abstract
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Toxoplasma gondii provokes rapid and sustained nuclear translocation of the signal transducer and activator of transcription 6 (STAT6) in HeLa cells. We observed activation of STAT6 as early as 2 hr after infection with T. gondii by the nuclear translocation of fluorescence expressed from exogenously transfected pDsRed2-STAT6 plasmid and by the detection of phosphotyrosine-STAT6 in Western blot. STAT6 activation occurred only by infection with live tachyzoites but not by co-culture with killed tachyzoites or soluble T. gondii extracts. STAT6 phosphorylation was inhibited by small interfering RNA of STAT6 (siSTAT6). In view of the fact that STAT6 is a central mediator of IL-4 induced gene expression, activation of STAT6 by T. gondii infection resembles that infected host cells has been stimulated by IL-4 treatment. STAT1 was affected to increase the transcription and expression by the treatment of siSTAT6. STAT6 activation was not affected by any excess SOCS's whereas that with IL-4 was inhibited by SOCS-1 and SOCS-3. T. gondii infection induced Eotaxin-3 gene expression which was reduced by IFN-γ. These results demonstrate that T. gondii exploits host STAT6 to take away various harmful reactions by IFN-γ. This shows, for the first time, IL-4-like action by T. gondii infection modulates microbicidal action by IFN-γ in infected cells.

Citations

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Nuclear Localization and Cleavage of STAT6 Is Induced by Kaposi’s Sarcoma-Associated Herpesvirus for Viral Latency
Chong Wang, Caixia Zhu, Fang Wei, Shujun Gao, Liming Zhang, Yuhong Li, Yanling Feng, Yin Tong, Jianqing Xu, Bin Wang, Zhenghong Yuan, Erle S. Robertson, Qiliang Cai, Paul D. Ling
PLOS Pathogens.2017; 13(1): e1006124. CrossRef
SAG5B and SAG5C combined vaccine protects mice against Toxoplasma gondii infection
Gang Lu, Jian Zhou, Aihua Zhou, Yali Han, Jingjing Guo, Pengxia Song, Huaiyu Zhou, Hua Cong, Ming Hou, Lin Wang, Shenyi He
Parasitology International.2017; 66(5): 596. CrossRef
SAG4 DNA and Peptide Vaccination Provides Partial Protection against T. gondii Infection in BALB/c Mice
Jian Zhou, Lin Wang
Frontiers in Microbiology.2017;[Epub] CrossRef
Afatinib Reduces STAT6 Signaling of Host ARPE-19 Cells Infected with Toxoplasma gondii
Zhaoshou Yang, Hye-Jin Ahn, Young-Hoon Park, Ho-Woo Nam
The Korean Journal of Parasitology.2016; 54(1): 31. CrossRef
Chronic Toxoplasmosis Modulates the Induction of Contact Hypersensitivity by TNCB in Mouse Model
Zhaoshou Yang, Hye-Jin Ahn, Ho-Woo Nam
The Korean Journal of Parasitology.2015; 53(6): 755. CrossRef
Activation of STAT6 by STING Is Critical for Antiviral Innate Immunity
Huihui Chen, Hui Sun, Fuping You, Wenxiang Sun, Xiang Zhou, Lu Chen, Jing Yang, Yutao Wang, Hong Tang, Yukun Guan, Weiwei Xia, Jun Gu, Hiroki Ishikawa, Delia Gutman, Glen Barber, Zhihai Qin, Zhengfan Jiang
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Deactivation of STAT6 through Serine 707 Phosphorylation by JNK
Takashi Shirakawa, Yoshinori Kawazoe, Tomoko Tsujikawa, Dongju Jung, Shin-ichi Sato, Motonari Uesugi
Journal of Biological Chemistry.2011; 286(5): 4003. CrossRef
Coactivator P100 Protein Enhances STAT6‐Dependent Transcriptional Activation But Has No Effect on STAT1‐Mediated Gene Transcription
Xinting Wang, Xin Liu, Jianfei Fang, Yanxin Lu, Jinyan He, Xuyang Yao, Zhi Yao, Jie Yang
The Anatomical Record.2010; 293(6): 1010. CrossRef
Toxoplasma Rhoptry Protein 16 (ROP16) Subverts Host Function by Direct Tyrosine Phosphorylation of STAT6
Yi-Ching Ong, Michael L. Reese, John C. Boothroyd
Journal of Biological Chemistry.2010; 285(37): 28731. CrossRef
STAT6 activation by Toxoplasma gondii infection induces the expression of Th2 C-C chemokine ligands and B clade serine protease inhibitors in macrophage
Hye-Jin Ahn, Ji Yeon Kim, Kyung-Ju Ryu, Ho-Woo Nam
Parasitology Research.2009; 105(5): 1445. CrossRef