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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

Schematic diagram of Tim-3–mediated negative regulation of the TLR response and promotion of Th2 bias at the maternal-fetal interface.(Left) LPS promotes Th1 bias at the maternal-fetal interface by activation of NF-κB and inhibition of IRF4. LPS can also induce apoptosis of DSCs. (Right) At the same time, LPS increases Tim-3 expression in DSCs, which in turn decreases DSC apoptosis and suppresses NF-κB activation mediated by LPS/TLR4 in an ERK1/2-dependent manner. Tim-3 not only increases basal IRF4 expression in DSCs but also abrogates LPS-induced IRF4 suppression, thus promoting Th2 bias at the maternal-fetal interface.
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f6: Schematic diagram of Tim-3–mediated negative regulation of the TLR response and promotion of Th2 bias at the maternal-fetal interface.(Left) LPS promotes Th1 bias at the maternal-fetal interface by activation of NF-κB and inhibition of IRF4. LPS can also induce apoptosis of DSCs. (Right) At the same time, LPS increases Tim-3 expression in DSCs, which in turn decreases DSC apoptosis and suppresses NF-κB activation mediated by LPS/TLR4 in an ERK1/2-dependent manner. Tim-3 not only increases basal IRF4 expression in DSCs but also abrogates LPS-induced IRF4 suppression, thus promoting Th2 bias at the maternal-fetal interface.

Mentions: The proposal model for Tim-3–mediated negative regulation of the TLR response and induction of Th2 bias in the decidual stromal cells are illustrated in Figure 6.


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)

Schematic diagram of Tim-3–mediated negative regulation of the TLR response and promotion of Th2 bias at the maternal-fetal interface.(Left) LPS promotes Th1 bias at the maternal-fetal interface by activation of NF-κB and inhibition of IRF4. LPS can also induce apoptosis of DSCs. (Right) At the same time, LPS increases Tim-3 expression in DSCs, which in turn decreases DSC apoptosis and suppresses NF-κB activation mediated by LPS/TLR4 in an ERK1/2-dependent manner. Tim-3 not only increases basal IRF4 expression in DSCs but also abrogates LPS-induced IRF4 suppression, thus promoting Th2 bias at the maternal-fetal interface.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4355741&req=5

f6: Schematic diagram of Tim-3–mediated negative regulation of the TLR response and promotion of Th2 bias at the maternal-fetal interface.(Left) LPS promotes Th1 bias at the maternal-fetal interface by activation of NF-κB and inhibition of IRF4. LPS can also induce apoptosis of DSCs. (Right) At the same time, LPS increases Tim-3 expression in DSCs, which in turn decreases DSC apoptosis and suppresses NF-κB activation mediated by LPS/TLR4 in an ERK1/2-dependent manner. Tim-3 not only increases basal IRF4 expression in DSCs but also abrogates LPS-induced IRF4 suppression, thus promoting Th2 bias at the maternal-fetal interface.
Mentions: The proposal model for Tim-3–mediated negative regulation of the TLR response and induction of Th2 bias in the decidual stromal cells are illustrated in Figure 6.

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