The Experts below are selected from a list of 1593 Experts worldwide ranked by ideXlab platform
Paul B. Rothman - One of the best experts on this subject based on the ideXlab platform.
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TH17 Cell Differentiation Is Regulated by the Circadian Clock
2016Co-Authors: Masaki Kashiwada, Paul B. Rothman, Joseph S. Takahashi, Lora V. HooperAbstract:Circadian clocks regulate numerous physiological processes that vary across the day-night (diurnal) cycle, but if and how the circadian clock regulates the adaptive immune system is mostly unclear. Interleukin-17–producing CD4+ T helper (TH17) cells are proinflammatory immune cells that protect against bacterial and fungal infections at mucosal surfaces. Their lineage specification is regulated by the orphan nuclear receptor RORgt. We show that the transcription factor NFIL3 suppresses TH17 cell development by directly binding and repressing the Rorgt promoter. NFIL3 links TH17 cell development to the circadian clock network through the transcription factor REV-ERBa. Accordingly, TH17 lineage specification varies diurnally and is altered in Rev-erba−/−mice. Light-cycle disruption elevated intestinal TH17 cell frequencies and increased susceptibility to inflammatory disease. Thus, lineage specification of a key immune cell is under direct circadian control. The development and function of the im-mune system is profoundly affected byenvironmental factors such as microor-ganisms (1, 2), nutrients (3), and light cues (4). Interleukin-17 (IL-17A and F)–producing CD4+ T helper (TH17) cells are a key immune cell lineage that protects against bacterial and funga
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NFIL3 deficient mice develop microbiota dependent il 12 23 driven spontaneous colitis
Journal of Immunology, 2014Co-Authors: Taku Kobayashi, Erin C. Steinbach, Steven M. Russo, Katsuyoshi Matsuoka, Tomonori Nochi, Nitsan Maharshak, Luke B. Borst, Bruce S. Hostager, Victor J Garciamartinez, Paul B. RothmanAbstract:NFIL3 is a transcription factor that regulates multiple immunologic functions. In myeloid cells, NFIL3 is IL-10 inducible and has a key role as a repressor of IL-12p40 transcription. NFIL3 is a susceptibility gene for the human inflammatory bowel diseases. In this article, we describe spontaneous colitis in NFIL3(-/-) mice. Mice lacking both NFIL3 and Il10 had severe early-onset colitis, suggesting that NFIL3 and IL-10 independently regulate mucosal homeostasis. Lymphocytes were necessary for colitis, because NFIL3/Rag1 double-knockout mice were protected from disease. However, NFIL3/Rag1 double-knockout mice adoptively transferred with wild-type CD4(+) T cells developed severe colitis compared with Rag1(-/-) recipients, suggesting that colitis was linked to defects in innate immune cells. Colitis was abrogated in NFIL3/Il12b double-deficient mice, identifying Il12b dysregulation as a central pathogenic event. Finally, germ-free NFIL3(-/-) mice do not develop colonic inflammation. Thus, NFIL3 is a microbiota-dependent, IL-10-independent regulator of mucosal homeostasis via IL-12p40.
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NFIL3 deficient mice develop microbiota dependent, IL-12/23 driven spontaneous colitis
Journal of immunology (Baltimore Md. : 1950), 2014Co-Authors: Taku Kobayashi, Erin C. Steinbach, Steven M. Russo, Katsuyoshi Matsuoka, Tomonori Nochi, Nitsan Maharshak, Luke B. Borst, Bruce S. Hostager, J. Victor Garcia-martinez, Paul B. RothmanAbstract:NFIL3 is a transcription factor that regulates multiple immunologic functions. In myeloid cells, NFIL3 is IL-10 inducible and has a key role as a repressor of IL-12p40 transcription. NFIL3 is a susceptibility gene for the human inflammatory bowel diseases. In this article, we describe spontaneous colitis in NFIL3(-/-) mice. Mice lacking both NFIL3 and Il10 had severe early-onset colitis, suggesting that NFIL3 and IL-10 independently regulate mucosal homeostasis. Lymphocytes were necessary for colitis, because NFIL3/Rag1 double-knockout mice were protected from disease. However, NFIL3/Rag1 double-knockout mice adoptively transferred with wild-type CD4(+) T cells developed severe colitis compared with Rag1(-/-) recipients, suggesting that colitis was linked to defects in innate immune cells. Colitis was abrogated in NFIL3/Il12b double-deficient mice, identifying Il12b dysregulation as a central pathogenic event. Finally, germ-free NFIL3(-/-) mice do not develop colonic inflammation. Thus, NFIL3 is a microbiota-dependent, IL-10-independent regulator of mucosal homeostasis via IL-12p40.
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NFIL3-independent lineage maintenance and antiviral response of natural killer cells
The Journal of experimental medicine, 2013Co-Authors: Matthew A. Firth, Paul B. Rothman, Georg Gasteiger, Sharline Madera, Aimee M. Beaulieu, Eliseo F. Castillo, Kimberly S. Schluns, Masato Kubo, Eric Vivier, Joseph C. SunAbstract:Development of the natural killer (NK) cell lineage is dependent on the transcription factor NFIL3 (or E4BP4), which is thought to act downstream of IL-15 signaling. NFIL3-deficient mice lack NK cells, whereas other lymphocyte lineages (B, T, and NKT cells) remain largely intact. We report the appearance of Ly49H-expressing NK cells in NFIL3−/− mice infected with mouse cytomegalovirus (MCMV) or recombinant viruses expressing the viral m157 glycoprotein. NFIL3−/− NK cells at the peak of antigen-driven expansion were functionally similar to NK cells from infected wild-type mice with respect to IFN-γ production and cytotoxicity, and could comparably produce long-lived memory NK cells that persisted in lymphoid and nonlymphoid tissues for >60 d. We demonstrate that generation and maintenance of NK cell memory is an NFIL3-independent but IL-15–dependent process. Furthermore, specific ablation of NFIL3 in either immature NK cells in the bone marrow or mature peripheral NK cells had no observable effect on NK cell lineage maintenance or homeostasis. Thus, expression of NFIL3 is crucial only early in the development of NK cells, and signals through activating receptors and proinflammatory cytokines during viral infection can bypass the requirement for NFIL3, promoting the proliferation and long-term survival of virus-specific NK cells.
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TH17 cell differentiation is regulated by the circadian clock.
Science (New York N.Y.), 2013Co-Authors: Darcy Rollins, Paul B. Rothman, Masaki Kashiwada, Kelly A. Ruhn, Jeremy J. Stubblefield, Carla B. Green, Joseph S. Takahashi, Lora V. HooperAbstract:Circadian clocks regulate numerous physiological processes that vary across the day-night (diurnal) cycle, but if and how the circadian clock regulates the adaptive immune system is mostly unclear. Interleukin-17-producing CD4(+) T helper (T(H)17) cells are proinflammatory immune cells that protect against bacterial and fungal infections at mucosal surfaces. Their lineage specification is regulated by the orphan nuclear receptor RORγt. We show that the transcription factor NFIL3 suppresses T(H)17 cell development by directly binding and repressing the Rorγt promoter. NFIL3 links T(H)17 cell development to the circadian clock network through the transcription factor REV-ERBα. Accordingly, TH17 lineage specification varies diurnally and is altered in Rev-erbα(-/-) mice. Light-cycle disruption elevated intestinal T(H)17 cell frequencies and increased susceptibility to inflammatory disease. Thus, lineage specification of a key immune cell is under direct circadian control.
Yi Zhang - One of the best experts on this subject based on the ideXlab platform.
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the stat3 NFIL3 signaling axis mediated chemotherapy resistance is reversed by raddeanin a via inducing apoptosis in choriocarcinoma cells
Journal of Cellular Physiology, 2018Co-Authors: Zheng Peng, Chun Zhang, Wenjun Zhou, Yi ZhangAbstract:Chemotherapy resistance is the major issue of choriocarcinoma. Apoptosis always is the ultimate outcome of chemotherapeutic drugs, which considered one of the reasons of resistance. We investigated the role of STAT3/NFIL3 signaling-inhibited apoptosis in chemotherapy resistance and whether Raddeanin A (RA) could be a new drug to reverse resistance. Established three drug-resistant cell lines as JEG-3/MTX, JEG-3/5-FU, and JEG-3/VP16. NFIL3 and STAT3 expression was evaluated in the cells. The IC50 value, apoptosis rate and apoptins were observed with transfection of siNFIL3, Lenti-OE™-NFIL3, shSTAT3, and Lenti-OE™-STAT3 or RA treatment. In addition, the luciferase reporter analysis and co-immunoprecipitation assays were used to investigate the relation of STAT3 and NFIL3. Hyper-activation of STAT3 and NFIL3 expression were observed in three drug-resistant cell lines. STAT3 enhanced NFIL3 transcriptional activity by binding the relative promoter region. Activated STAT3/NFIL3 pathway caused low rate of apoptosis which resulted in chemotherapy resistance. RA reduced the resistance index of resistant cells and induced caspase 3 dependent apoptosis, meanwhile it repressed the STAT3/NFIL3 activation. STAT3/NFIL3 axis-inhibited apoptosis is a novel mechanism of chemotherapy resistance in choriocarcinoma. With the suppression of STAT3/NFIL3 axis and apoptosis induction, RA is a potential agent or lead candidate for improving chemotherapy.
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The STAT3/NFIL3 signaling axis-mediated chemotherapy resistance is reversed by Raddeanin A via inducing apoptosis in choriocarcinoma cells.
Journal of cellular physiology, 2018Co-Authors: Zheng Peng, Chun Zhang, Wenjun Zhou, Yi ZhangAbstract:Chemotherapy resistance is the major issue of choriocarcinoma. Apoptosis always is the ultimate outcome of chemotherapeutic drugs, which considered one of the reasons of resistance. We investigated the role of STAT3/NFIL3 signaling-inhibited apoptosis in chemotherapy resistance and whether Raddeanin A (RA) could be a new drug to reverse resistance. Established three drug-resistant cell lines as JEG-3/MTX, JEG-3/5-FU, and JEG-3/VP16. NFIL3 and STAT3 expression was evaluated in the cells. The IC50 value, apoptosis rate and apoptins were observed with transfection of siNFIL3, Lenti-OE™-NFIL3, shSTAT3, and Lenti-OE™-STAT3 or RA treatment. In addition, the luciferase reporter analysis and co-immunoprecipitation assays were used to investigate the relation of STAT3 and NFIL3. Hyper-activation of STAT3 and NFIL3 expression were observed in three drug-resistant cell lines. STAT3 enhanced NFIL3 transcriptional activity by binding the relative promoter region. Activated STAT3/NFIL3 pathway caused low rate of apoptosis which resulted in chemotherapy resistance. RA reduced the resistance index of resistant cells and induced caspase 3 dependent apoptosis, meanwhile it repressed the STAT3/NFIL3 activation. STAT3/NFIL3 axis-inhibited apoptosis is a novel mechanism of chemotherapy resistance in choriocarcinoma. With the suppression of STAT3/NFIL3 axis and apoptosis induction, RA is a potential agent or lead candidate for improving chemotherapy.
Chen Zhu - One of the best experts on this subject based on the ideXlab platform.
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An IL-27/NFIL3 signaling axis drives Tim-3 and IL-10 expression and T cell dysfunction
2016Co-Authors: Chen Zhu, Kaori Sakuishi, Sheng Xiao, Zhiyi Sun, Sarah Zaghouani, Chao Wang, Dewar J. Tan, Manu RangachariAbstract:The inhibitory receptor Tim-3 has emerged as a critical regulator of the T cell dysfunction that develops in chronic viral infections and cancers. However, little is known regarding the signaling pathways that drive Tim-3 expression. Here, we demonstrate that IL-27 induces NFIL3, which promotes permissive chromatin remodeling of the Tim-3 locus and induces Tim-3 expression together with the immunosuppressive cytokine IL-10. We further show that the IL-27/NFIL3 signaling axis is crucial for the induction of Tim-3 in vivo. IL-27-conditioned Th1 cells exhibit reduced effector function and are poor mediators of intestinal inflammation. This inhibitory effect is NFIL3 dependent. In contrast, tumor-infiltrating lymphocytes (TILs) from IL-27R−/ − mice exhibit reduced NFIL3, less Tim-3 expression and failure to develop dysfunctional phenotype, resulting in better tumor growth control. Thus, our data identify an IL-27/NFIL3 signaling axis as a key regulator of effector T cell responses via induction of Tim-3, IL-10, and T cell dysfunction
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An IL-27/NFIL3 signalling axis drives Tim-3 and IL-10 expression and T-cell dysfunction.
Nature communications, 2015Co-Authors: Chen Zhu, Kaori Sakuishi, Sheng Xiao, Zhiyi Sun, Sarah Zaghouani, Chao Wang, Dewar J. Tan, Manu RangachariAbstract:The inhibitory receptor T-cell immunoglobulin and mucin domain-3 (Tim-3) has emerged as a critical regulator of the T-cell dysfunction that develops in chronic viral infections and cancers. However, little is known regarding the signalling pathways that drive Tim-3 expression. Here, we demonstrate that interleukin (IL)-27 induces nuclear factor, interleukin 3 regulated (NFIL3), which promotes permissive chromatin remodelling of the Tim-3 locus and induces Tim-3 expression together with the immunosuppressive cytokine IL-10. We further show that the IL-27/NFIL3 signalling axis is crucial for the induction of Tim-3 in vivo. IL-27-conditioned T helper 1 cells exhibit reduced effector function and are poor mediators of intestinal inflammation. This inhibitory effect is NFIL3 dependent. In contrast, tumour-infiltrating lymphocytes from IL-27R(-/-) mice exhibit reduced NFIL3, less Tim-3 expression and failure to develop dysfunctional phenotype, resulting in better tumour growth control. Thus, our data identify an IL-27/NFIL3 signalling axis as a key regulator of effector T-cell responses via induction of Tim-3, IL-10 and T-cell dysfunction.
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corrigendum an il 27 NFIL3 signalling axis drives tim 3 and il 10 expression and t cell dysfunction
Nature Communications, 2015Co-Authors: Chen Zhu, Kaori Sakuishi, Sheng Xiao, Zhiyi Sun, Sarah Zaghouani, Chao Wang, Dewar J. Tan, Manu Rangachari, Thomas Pertel, Hyuntak JinAbstract:Corrigendum: An IL-27/NFIL3 signalling axis drives Tim-3 and IL–10 expression and T-cell dysfunction
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an il 27 NFIL3 signalling axis drives tim 3 and il 10 expression and t cell dysfunction
Nature Communications, 2015Co-Authors: Chen Zhu, Kaori Sakuishi, Sheng Xiao, Zhiyi Sun, Sarah Zaghouani, Chao Wang, Dewar J. Tan, Manu Rangachari, Thomas Pertel, Hyuntak JinAbstract:The inhibitory receptor T-cell immunoglobulin and mucin domain-3 (Tim-3) has emerged as a critical regulator of the T-cell dysfunction that develops in chronic viral infections and cancers. However, little is known regarding the signalling pathways that drive Tim-3 expression. Here, we demonstrate that interleukin (IL)-27 induces nuclear factor, interleukin 3 regulated (NFIL3), which promotes permissive chromatin remodelling of the Tim-3 locus and induces Tim-3 expression together with the immunosuppressive cytokine IL-10. We further show that the IL-27/NFIL3 signalling axis is crucial for the induction of Tim-3 in vivo. IL-27-conditioned T helper 1 cells exhibit reduced effector function and are poor mediators of intestinal inflammation. This inhibitory effect is NFIL3 dependent. In contrast, tumour-infiltrating lymphocytes from IL-27R(-/-) mice exhibit reduced NFIL3, less Tim-3 expression and failure to develop dysfunctional phenotype, resulting in better tumour growth control. Thus, our data identify an IL-27/NFIL3 signalling axis as a key regulator of effector T-cell responses via induction of Tim-3, IL-10 and T-cell dysfunction.
Manu Rangachari - One of the best experts on this subject based on the ideXlab platform.
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An IL-27/NFIL3 signaling axis drives Tim-3 and IL-10 expression and T cell dysfunction
2016Co-Authors: Chen Zhu, Kaori Sakuishi, Sheng Xiao, Zhiyi Sun, Sarah Zaghouani, Chao Wang, Dewar J. Tan, Manu RangachariAbstract:The inhibitory receptor Tim-3 has emerged as a critical regulator of the T cell dysfunction that develops in chronic viral infections and cancers. However, little is known regarding the signaling pathways that drive Tim-3 expression. Here, we demonstrate that IL-27 induces NFIL3, which promotes permissive chromatin remodeling of the Tim-3 locus and induces Tim-3 expression together with the immunosuppressive cytokine IL-10. We further show that the IL-27/NFIL3 signaling axis is crucial for the induction of Tim-3 in vivo. IL-27-conditioned Th1 cells exhibit reduced effector function and are poor mediators of intestinal inflammation. This inhibitory effect is NFIL3 dependent. In contrast, tumor-infiltrating lymphocytes (TILs) from IL-27R−/ − mice exhibit reduced NFIL3, less Tim-3 expression and failure to develop dysfunctional phenotype, resulting in better tumor growth control. Thus, our data identify an IL-27/NFIL3 signaling axis as a key regulator of effector T cell responses via induction of Tim-3, IL-10, and T cell dysfunction
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An IL-27/NFIL3 signalling axis drives Tim-3 and IL-10 expression and T-cell dysfunction.
Nature communications, 2015Co-Authors: Chen Zhu, Kaori Sakuishi, Sheng Xiao, Zhiyi Sun, Sarah Zaghouani, Chao Wang, Dewar J. Tan, Manu RangachariAbstract:The inhibitory receptor T-cell immunoglobulin and mucin domain-3 (Tim-3) has emerged as a critical regulator of the T-cell dysfunction that develops in chronic viral infections and cancers. However, little is known regarding the signalling pathways that drive Tim-3 expression. Here, we demonstrate that interleukin (IL)-27 induces nuclear factor, interleukin 3 regulated (NFIL3), which promotes permissive chromatin remodelling of the Tim-3 locus and induces Tim-3 expression together with the immunosuppressive cytokine IL-10. We further show that the IL-27/NFIL3 signalling axis is crucial for the induction of Tim-3 in vivo. IL-27-conditioned T helper 1 cells exhibit reduced effector function and are poor mediators of intestinal inflammation. This inhibitory effect is NFIL3 dependent. In contrast, tumour-infiltrating lymphocytes from IL-27R(-/-) mice exhibit reduced NFIL3, less Tim-3 expression and failure to develop dysfunctional phenotype, resulting in better tumour growth control. Thus, our data identify an IL-27/NFIL3 signalling axis as a key regulator of effector T-cell responses via induction of Tim-3, IL-10 and T-cell dysfunction.
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corrigendum an il 27 NFIL3 signalling axis drives tim 3 and il 10 expression and t cell dysfunction
Nature Communications, 2015Co-Authors: Chen Zhu, Kaori Sakuishi, Sheng Xiao, Zhiyi Sun, Sarah Zaghouani, Chao Wang, Dewar J. Tan, Manu Rangachari, Thomas Pertel, Hyuntak JinAbstract:Corrigendum: An IL-27/NFIL3 signalling axis drives Tim-3 and IL–10 expression and T-cell dysfunction
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an il 27 NFIL3 signalling axis drives tim 3 and il 10 expression and t cell dysfunction
Nature Communications, 2015Co-Authors: Chen Zhu, Kaori Sakuishi, Sheng Xiao, Zhiyi Sun, Sarah Zaghouani, Chao Wang, Dewar J. Tan, Manu Rangachari, Thomas Pertel, Hyuntak JinAbstract:The inhibitory receptor T-cell immunoglobulin and mucin domain-3 (Tim-3) has emerged as a critical regulator of the T-cell dysfunction that develops in chronic viral infections and cancers. However, little is known regarding the signalling pathways that drive Tim-3 expression. Here, we demonstrate that interleukin (IL)-27 induces nuclear factor, interleukin 3 regulated (NFIL3), which promotes permissive chromatin remodelling of the Tim-3 locus and induces Tim-3 expression together with the immunosuppressive cytokine IL-10. We further show that the IL-27/NFIL3 signalling axis is crucial for the induction of Tim-3 in vivo. IL-27-conditioned T helper 1 cells exhibit reduced effector function and are poor mediators of intestinal inflammation. This inhibitory effect is NFIL3 dependent. In contrast, tumour-infiltrating lymphocytes from IL-27R(-/-) mice exhibit reduced NFIL3, less Tim-3 expression and failure to develop dysfunctional phenotype, resulting in better tumour growth control. Thus, our data identify an IL-27/NFIL3 signalling axis as a key regulator of effector T-cell responses via induction of Tim-3, IL-10 and T-cell dysfunction.
Zheng Peng - One of the best experts on this subject based on the ideXlab platform.
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the stat3 NFIL3 signaling axis mediated chemotherapy resistance is reversed by raddeanin a via inducing apoptosis in choriocarcinoma cells
Journal of Cellular Physiology, 2018Co-Authors: Zheng Peng, Chun Zhang, Wenjun Zhou, Yi ZhangAbstract:Chemotherapy resistance is the major issue of choriocarcinoma. Apoptosis always is the ultimate outcome of chemotherapeutic drugs, which considered one of the reasons of resistance. We investigated the role of STAT3/NFIL3 signaling-inhibited apoptosis in chemotherapy resistance and whether Raddeanin A (RA) could be a new drug to reverse resistance. Established three drug-resistant cell lines as JEG-3/MTX, JEG-3/5-FU, and JEG-3/VP16. NFIL3 and STAT3 expression was evaluated in the cells. The IC50 value, apoptosis rate and apoptins were observed with transfection of siNFIL3, Lenti-OE™-NFIL3, shSTAT3, and Lenti-OE™-STAT3 or RA treatment. In addition, the luciferase reporter analysis and co-immunoprecipitation assays were used to investigate the relation of STAT3 and NFIL3. Hyper-activation of STAT3 and NFIL3 expression were observed in three drug-resistant cell lines. STAT3 enhanced NFIL3 transcriptional activity by binding the relative promoter region. Activated STAT3/NFIL3 pathway caused low rate of apoptosis which resulted in chemotherapy resistance. RA reduced the resistance index of resistant cells and induced caspase 3 dependent apoptosis, meanwhile it repressed the STAT3/NFIL3 activation. STAT3/NFIL3 axis-inhibited apoptosis is a novel mechanism of chemotherapy resistance in choriocarcinoma. With the suppression of STAT3/NFIL3 axis and apoptosis induction, RA is a potential agent or lead candidate for improving chemotherapy.
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The STAT3/NFIL3 signaling axis-mediated chemotherapy resistance is reversed by Raddeanin A via inducing apoptosis in choriocarcinoma cells.
Journal of cellular physiology, 2018Co-Authors: Zheng Peng, Chun Zhang, Wenjun Zhou, Yi ZhangAbstract:Chemotherapy resistance is the major issue of choriocarcinoma. Apoptosis always is the ultimate outcome of chemotherapeutic drugs, which considered one of the reasons of resistance. We investigated the role of STAT3/NFIL3 signaling-inhibited apoptosis in chemotherapy resistance and whether Raddeanin A (RA) could be a new drug to reverse resistance. Established three drug-resistant cell lines as JEG-3/MTX, JEG-3/5-FU, and JEG-3/VP16. NFIL3 and STAT3 expression was evaluated in the cells. The IC50 value, apoptosis rate and apoptins were observed with transfection of siNFIL3, Lenti-OE™-NFIL3, shSTAT3, and Lenti-OE™-STAT3 or RA treatment. In addition, the luciferase reporter analysis and co-immunoprecipitation assays were used to investigate the relation of STAT3 and NFIL3. Hyper-activation of STAT3 and NFIL3 expression were observed in three drug-resistant cell lines. STAT3 enhanced NFIL3 transcriptional activity by binding the relative promoter region. Activated STAT3/NFIL3 pathway caused low rate of apoptosis which resulted in chemotherapy resistance. RA reduced the resistance index of resistant cells and induced caspase 3 dependent apoptosis, meanwhile it repressed the STAT3/NFIL3 activation. STAT3/NFIL3 axis-inhibited apoptosis is a novel mechanism of chemotherapy resistance in choriocarcinoma. With the suppression of STAT3/NFIL3 axis and apoptosis induction, RA is a potential agent or lead candidate for improving chemotherapy.