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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 protected DSCs from TLR-mediated apoptosis through activation of the ERK1/2 pathway.(A) Quantitation of flow cytometric analysis of Tim-3 expression in DSCs stimulated with the indicated concentrations of LPS. (B) Flow cytometric analysis (right) and quantitation (left) of apoptosis based on annexin expression and PI staining in DSCs stimulated with LPS (10 ng/ml) in the presence or absence of Tim-3 and anti–Tim-3 mAb. Treatment group numbers below histogram bars correspond to numbers on panels of flow cytometry plot. (C) Flow cytometric analysis (right) and quantitation (left) of apoptosis in DSCs after treatment with Tim-3 in the presence or absence of the indicated inhibitors of signal transduction. (D) In-cell western analysis (lower) and quantitation (upper) of the level of ERK1/2 phosphorylation relative to total ERK1/2 in DSCs treated with Tim-3 for the indicated times. Images are representative of six individual experiments. Data represent mean ± SEM. Flow cytometry plot is from one representative experiment; n = 18 DSC cells in the first trimester of normal pregnancy. *P < 0.5, **P < 0.01, ***P < 0.001, compared with group 1; ΔP < 0.5, ΔΔP < 0.01, ΔΔΔP < 0.001, compared with group 2; #P < 0.5, ##P < 0.01, ###P < 0.001, compared with group 3.
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f3: Tim-3 protected DSCs from TLR-mediated apoptosis through activation of the ERK1/2 pathway.(A) Quantitation of flow cytometric analysis of Tim-3 expression in DSCs stimulated with the indicated concentrations of LPS. (B) Flow cytometric analysis (right) and quantitation (left) of apoptosis based on annexin expression and PI staining in DSCs stimulated with LPS (10 ng/ml) in the presence or absence of Tim-3 and anti–Tim-3 mAb. Treatment group numbers below histogram bars correspond to numbers on panels of flow cytometry plot. (C) Flow cytometric analysis (right) and quantitation (left) of apoptosis in DSCs after treatment with Tim-3 in the presence or absence of the indicated inhibitors of signal transduction. (D) In-cell western analysis (lower) and quantitation (upper) of the level of ERK1/2 phosphorylation relative to total ERK1/2 in DSCs treated with Tim-3 for the indicated times. Images are representative of six individual experiments. Data represent mean ± SEM. Flow cytometry plot is from one representative experiment; n = 18 DSC cells in the first trimester of normal pregnancy. *P < 0.5, **P < 0.01, ***P < 0.001, compared with group 1; ΔP < 0.5, ΔΔP < 0.01, ΔΔΔP < 0.001, compared with group 2; #P < 0.5, ##P < 0.01, ###P < 0.001, compared with group 3.

Mentions: As noted previously, Tim-3 is involved in the regulation of TLR signal-mediated inflammatory reaction and damage151617. Given that Tim-3 expression in DSCs was significantly decreased in miscarriage compared with normal pregnancy, and stimulation of DSCs with ligands of different TLRs resulted in up-regulation of Tim-3 expression (Figure 3A and Figure S2A), we hypothesized that, during normal pregnancy, Tim-3 provides protection from TLR-mediated damage.


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 protected DSCs from TLR-mediated apoptosis through activation of the ERK1/2 pathway.(A) Quantitation of flow cytometric analysis of Tim-3 expression in DSCs stimulated with the indicated concentrations of LPS. (B) Flow cytometric analysis (right) and quantitation (left) of apoptosis based on annexin expression and PI staining in DSCs stimulated with LPS (10 ng/ml) in the presence or absence of Tim-3 and anti–Tim-3 mAb. Treatment group numbers below histogram bars correspond to numbers on panels of flow cytometry plot. (C) Flow cytometric analysis (right) and quantitation (left) of apoptosis in DSCs after treatment with Tim-3 in the presence or absence of the indicated inhibitors of signal transduction. (D) In-cell western analysis (lower) and quantitation (upper) of the level of ERK1/2 phosphorylation relative to total ERK1/2 in DSCs treated with Tim-3 for the indicated times. Images are representative of six individual experiments. Data represent mean ± SEM. Flow cytometry plot is from one representative experiment; n = 18 DSC cells in the first trimester of normal pregnancy. *P < 0.5, **P < 0.01, ***P < 0.001, compared with group 1; ΔP < 0.5, ΔΔP < 0.01, ΔΔΔP < 0.001, compared with group 2; #P < 0.5, ##P < 0.01, ###P < 0.001, compared with group 3.
© Copyright Policy - open-access
Related In: Results  -  Collection

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f3: Tim-3 protected DSCs from TLR-mediated apoptosis through activation of the ERK1/2 pathway.(A) Quantitation of flow cytometric analysis of Tim-3 expression in DSCs stimulated with the indicated concentrations of LPS. (B) Flow cytometric analysis (right) and quantitation (left) of apoptosis based on annexin expression and PI staining in DSCs stimulated with LPS (10 ng/ml) in the presence or absence of Tim-3 and anti–Tim-3 mAb. Treatment group numbers below histogram bars correspond to numbers on panels of flow cytometry plot. (C) Flow cytometric analysis (right) and quantitation (left) of apoptosis in DSCs after treatment with Tim-3 in the presence or absence of the indicated inhibitors of signal transduction. (D) In-cell western analysis (lower) and quantitation (upper) of the level of ERK1/2 phosphorylation relative to total ERK1/2 in DSCs treated with Tim-3 for the indicated times. Images are representative of six individual experiments. Data represent mean ± SEM. Flow cytometry plot is from one representative experiment; n = 18 DSC cells in the first trimester of normal pregnancy. *P < 0.5, **P < 0.01, ***P < 0.001, compared with group 1; ΔP < 0.5, ΔΔP < 0.01, ΔΔΔP < 0.001, compared with group 2; #P < 0.5, ##P < 0.01, ###P < 0.001, compared with group 3.
Mentions: As noted previously, Tim-3 is involved in the regulation of TLR signal-mediated inflammatory reaction and damage151617. Given that Tim-3 expression in DSCs was significantly decreased in miscarriage compared with normal pregnancy, and stimulation of DSCs with ligands of different TLRs resulted in up-regulation of Tim-3 expression (Figure 3A and Figure S2A), we hypothesized that, during normal pregnancy, Tim-3 provides protection from TLR-mediated damage.

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