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Tim-3 protects decidual stromal cells from toll-like receptor-mediated apoptosis and inflammatory reactions and promotes Th2 bias at the maternal-fetal interface.

Wang S, Cao C, Piao H, Li Y, Tao Y, Zhang X, Zhang D, Sun C, Zhu R, Wang Y, Yuan M, Li D, Du M - Sci Rep (2015)

Bottom Line: Here, we demonstrated significantly lowered expression of T-cell immunoglobulin and mucin domain 3 (Tim-3) in miscarried decidual stromal cells (DSCs), indicating that Tim-3 might play important roles in maintaining successful pregnancies.Tim-3 increased production of T helper 2 (Th2)-type cytokines by DSCs and reversed the inhibitory effect of LPS on Th2 cytokine generation by up-regulation of interferon regulatory factor 4 expression.Tim-3 blockade abolished the effect of Tim-3 on the inflammatory response to LPS stimulation.

View Article: PubMed Central - PubMed

Affiliation: Laboratory for Reproductive Immunology, Hospital and Institute of Obstetrics and Gynecology, Fudan University Shanghai Medical College, Shanghai 200011, China; Shanghai Key Laboratory of Female Reproductive Endocrine Related Diseases, Shanghai, 200011, China.

ABSTRACT
Toll-like receptors (TLRs) are important in mediating immune responses against various pathogens during pregnancy. However, uncontrolled TLR-triggered inflammation will endanger normal pregnancy, resulting in pregnancy loss. Therefore, maintenance of a moderate inflammatory response is crucial for successful pregnancy under conditions of infection. Here, we demonstrated significantly lowered expression of T-cell immunoglobulin and mucin domain 3 (Tim-3) in miscarried decidual stromal cells (DSCs), indicating that Tim-3 might play important roles in maintaining successful pregnancies. Activation of TLR signaling induced pro-inflammatory cytokine production and apoptosis of DSCs, which was accompanied by up-regulated Tim-3 expression. Tim-3, in turn, protected DSCs from TLR-mediated apoptosis in an ERK1/2 pathway-dependent manner. In addition, Tim-3 inhibited TLR signaling-induced inflammatory cytokine production by DSCs through suppressing NF-κB activation. Tim-3 increased production of T helper 2 (Th2)-type cytokines by DSCs and reversed the inhibitory effect of LPS on Th2 cytokine generation by up-regulation of interferon regulatory factor 4 expression. Tim-3 blockade abolished the effect of Tim-3 on the inflammatory response to LPS stimulation. Thus, Tim-3 signaling could represent a "self-control" mechanism in TLR-triggered inflammation during pregnancy. These findings identify Tim-3 as a key regulator of DSCs and suggest its potential as a target for the treatment of spontaneous abortion.

No MeSH data available.


Related in: MedlinePlus

Tim-3 downregulation correlated with human miscarriage.(A)Real-time PCR analysis of Tim-3 mRNA in human first trimester decidual tissue and DSCs. β-actin served as internal control. (B) Immunohistochemical localization of Tim-3 in decidual tissue from normal pregnancy and miscarriage. (C) Flow cytometric analysis (left) and quantitation (right) of Tim-3 expression in DSCs from normal pregnancy (n = 48) and miscarriage (abnormal pregnancy; n = 32). NP: normal pregnancy; AP: abnormal pregnancy. (D) Flow cytometric analysis and quantitation of IRF4 expression in Tim-3+ and Tim-3− DSCs (upper) and in DSCs in normal pregnancy treated with Tim-3, anti-Tim-3 mAb, or isotype-control IgG (Ctrl); n = 12 (lower). (E) Flow cytometric analysis (lower) and quantitation (upper) of production of the indicated Th2-type cytokines by Tim-3+ and Tim-3− DSCs of normal pregnancy; n = 18. Data represent mean ± standard error of the mean (SEM). The representative flow cytometry plots are from one representative experiment. *P ≤ 0.05, ***P ≤ 0.001.
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f1: Tim-3 downregulation correlated with human miscarriage.(A)Real-time PCR analysis of Tim-3 mRNA in human first trimester decidual tissue and DSCs. β-actin served as internal control. (B) Immunohistochemical localization of Tim-3 in decidual tissue from normal pregnancy and miscarriage. (C) Flow cytometric analysis (left) and quantitation (right) of Tim-3 expression in DSCs from normal pregnancy (n = 48) and miscarriage (abnormal pregnancy; n = 32). NP: normal pregnancy; AP: abnormal pregnancy. (D) Flow cytometric analysis and quantitation of IRF4 expression in Tim-3+ and Tim-3− DSCs (upper) and in DSCs in normal pregnancy treated with Tim-3, anti-Tim-3 mAb, or isotype-control IgG (Ctrl); n = 12 (lower). (E) Flow cytometric analysis (lower) and quantitation (upper) of production of the indicated Th2-type cytokines by Tim-3+ and Tim-3− DSCs of normal pregnancy; n = 18. Data represent mean ± standard error of the mean (SEM). The representative flow cytometry plots are from one representative experiment. *P ≤ 0.05, ***P ≤ 0.001.

Mentions: Tim-3 is an important immune regulatory molecule. To investigate whether the Tim-3 pathway is also involved in maternal-fetal tolerance, we first examined the expression of Tim-3 in deciduae from human first trimester pregnancy, and whether there was a correlation between Tim-3 expression and pregnancy outcome. As shown in Figure 1A, 1B and 1C, both Tim-3 mRNA and protein were detected in both decidual tissue and DSCs. Interestingly, a higher level of Tim-3 expression was observed in decidual tissue (Figure 1B) and DSCs (Figure 1C) from normal pregnancy than from miscarriage. Because Th2 bias at the maternal-fetal interface is crucial for maintenance of normal pregnancy, and because interferon regulatory factor 4 (IRF4) is a transcription factor important for Th2 bias, we further investigated the correlation between Tim-3 signal and IRF-4 expression20. Figure 1D (upper) shows notably increased IRF4 expression in Tim-3+ DSCs. Furthermore, treatment of DSCs with Tim-3 markedly up-regulated the expression of IRF4, whereas anti–Tim-3 mAb treatment down-regulated IRF4 expression in DSCs (Figure 1D, lower). We then directly measured Th2 cytokine production by Tim-3+ and Tim-3− DSCs. Consistently, Tim-3+ DSCs produced higher levels of Th2 cytokines than Tim-3− DSCs (Figure 1E). These findings suggest a correlation between low levels of Tim-3 and spontaneous abortion.


Tim-3 protects decidual stromal cells from toll-like receptor-mediated apoptosis and inflammatory reactions and promotes Th2 bias at the maternal-fetal interface.

Wang S, Cao C, Piao H, Li Y, Tao Y, Zhang X, Zhang D, Sun C, Zhu R, Wang Y, Yuan M, Li D, Du M - Sci Rep (2015)

Tim-3 downregulation correlated with human miscarriage.(A)Real-time PCR analysis of Tim-3 mRNA in human first trimester decidual tissue and DSCs. β-actin served as internal control. (B) Immunohistochemical localization of Tim-3 in decidual tissue from normal pregnancy and miscarriage. (C) Flow cytometric analysis (left) and quantitation (right) of Tim-3 expression in DSCs from normal pregnancy (n = 48) and miscarriage (abnormal pregnancy; n = 32). NP: normal pregnancy; AP: abnormal pregnancy. (D) Flow cytometric analysis and quantitation of IRF4 expression in Tim-3+ and Tim-3− DSCs (upper) and in DSCs in normal pregnancy treated with Tim-3, anti-Tim-3 mAb, or isotype-control IgG (Ctrl); n = 12 (lower). (E) Flow cytometric analysis (lower) and quantitation (upper) of production of the indicated Th2-type cytokines by Tim-3+ and Tim-3− DSCs of normal pregnancy; n = 18. Data represent mean ± standard error of the mean (SEM). The representative flow cytometry plots are from one representative experiment. *P ≤ 0.05, ***P ≤ 0.001.
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Related In: Results  -  Collection

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f1: Tim-3 downregulation correlated with human miscarriage.(A)Real-time PCR analysis of Tim-3 mRNA in human first trimester decidual tissue and DSCs. β-actin served as internal control. (B) Immunohistochemical localization of Tim-3 in decidual tissue from normal pregnancy and miscarriage. (C) Flow cytometric analysis (left) and quantitation (right) of Tim-3 expression in DSCs from normal pregnancy (n = 48) and miscarriage (abnormal pregnancy; n = 32). NP: normal pregnancy; AP: abnormal pregnancy. (D) Flow cytometric analysis and quantitation of IRF4 expression in Tim-3+ and Tim-3− DSCs (upper) and in DSCs in normal pregnancy treated with Tim-3, anti-Tim-3 mAb, or isotype-control IgG (Ctrl); n = 12 (lower). (E) Flow cytometric analysis (lower) and quantitation (upper) of production of the indicated Th2-type cytokines by Tim-3+ and Tim-3− DSCs of normal pregnancy; n = 18. Data represent mean ± standard error of the mean (SEM). The representative flow cytometry plots are from one representative experiment. *P ≤ 0.05, ***P ≤ 0.001.
Mentions: Tim-3 is an important immune regulatory molecule. To investigate whether the Tim-3 pathway is also involved in maternal-fetal tolerance, we first examined the expression of Tim-3 in deciduae from human first trimester pregnancy, and whether there was a correlation between Tim-3 expression and pregnancy outcome. As shown in Figure 1A, 1B and 1C, both Tim-3 mRNA and protein were detected in both decidual tissue and DSCs. Interestingly, a higher level of Tim-3 expression was observed in decidual tissue (Figure 1B) and DSCs (Figure 1C) from normal pregnancy than from miscarriage. Because Th2 bias at the maternal-fetal interface is crucial for maintenance of normal pregnancy, and because interferon regulatory factor 4 (IRF4) is a transcription factor important for Th2 bias, we further investigated the correlation between Tim-3 signal and IRF-4 expression20. Figure 1D (upper) shows notably increased IRF4 expression in Tim-3+ DSCs. Furthermore, treatment of DSCs with Tim-3 markedly up-regulated the expression of IRF4, whereas anti–Tim-3 mAb treatment down-regulated IRF4 expression in DSCs (Figure 1D, lower). We then directly measured Th2 cytokine production by Tim-3+ and Tim-3− DSCs. Consistently, Tim-3+ DSCs produced higher levels of Th2 cytokines than Tim-3− DSCs (Figure 1E). These findings suggest a correlation between low levels of Tim-3 and spontaneous abortion.

Bottom Line: Here, we demonstrated significantly lowered expression of T-cell immunoglobulin and mucin domain 3 (Tim-3) in miscarried decidual stromal cells (DSCs), indicating that Tim-3 might play important roles in maintaining successful pregnancies.Tim-3 increased production of T helper 2 (Th2)-type cytokines by DSCs and reversed the inhibitory effect of LPS on Th2 cytokine generation by up-regulation of interferon regulatory factor 4 expression.Tim-3 blockade abolished the effect of Tim-3 on the inflammatory response to LPS stimulation.

View Article: PubMed Central - PubMed

Affiliation: Laboratory for Reproductive Immunology, Hospital and Institute of Obstetrics and Gynecology, Fudan University Shanghai Medical College, Shanghai 200011, China; Shanghai Key Laboratory of Female Reproductive Endocrine Related Diseases, Shanghai, 200011, China.

ABSTRACT
Toll-like receptors (TLRs) are important in mediating immune responses against various pathogens during pregnancy. However, uncontrolled TLR-triggered inflammation will endanger normal pregnancy, resulting in pregnancy loss. Therefore, maintenance of a moderate inflammatory response is crucial for successful pregnancy under conditions of infection. Here, we demonstrated significantly lowered expression of T-cell immunoglobulin and mucin domain 3 (Tim-3) in miscarried decidual stromal cells (DSCs), indicating that Tim-3 might play important roles in maintaining successful pregnancies. Activation of TLR signaling induced pro-inflammatory cytokine production and apoptosis of DSCs, which was accompanied by up-regulated Tim-3 expression. Tim-3, in turn, protected DSCs from TLR-mediated apoptosis in an ERK1/2 pathway-dependent manner. In addition, Tim-3 inhibited TLR signaling-induced inflammatory cytokine production by DSCs through suppressing NF-κB activation. Tim-3 increased production of T helper 2 (Th2)-type cytokines by DSCs and reversed the inhibitory effect of LPS on Th2 cytokine generation by up-regulation of interferon regulatory factor 4 expression. Tim-3 blockade abolished the effect of Tim-3 on the inflammatory response to LPS stimulation. Thus, Tim-3 signaling could represent a "self-control" mechanism in TLR-triggered inflammation during pregnancy. These findings identify Tim-3 as a key regulator of DSCs and suggest its potential as a target for the treatment of spontaneous abortion.

No MeSH data available.


Related in: MedlinePlus