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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 promotes Th2 bias at the maternal-fetal interface.(A and B) Flow cytometric analysis of production of the indicated cytokines (A) and IRF4+ (B) by DSCs after stimulation with or without LPS (10 ng/ml) in the presence or absence of Tim-3 or anti-Tim-3 mAb. Data represent mean ± SEM. n = 10 DSCs in the first trimester of normal pregnancy. *P < 0.5, **P < 0.01, ***P < 0.001.
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f5: Tim-3 promotes Th2 bias at the maternal-fetal interface.(A and B) Flow cytometric analysis of production of the indicated cytokines (A) and IRF4+ (B) by DSCs after stimulation with or without LPS (10 ng/ml) in the presence or absence of Tim-3 or anti-Tim-3 mAb. Data represent mean ± SEM. n = 10 DSCs in the first trimester of normal pregnancy. *P < 0.5, **P < 0.01, ***P < 0.001.

Mentions: It has been reported that TLR-induced pregnancy loss can be prevented by maternal administration of the immuno-regulatory cytokine, IL-10321. Given that Tim-3 suppressed LPS-induced pro-inflammatory cytokine production and that Tim-3+ DSCs produced higher levels of Th2 cytokines than Tim-3− cells, we wondered whether Tim-3 affected Th2 cytokine production by DSCs upon LPS stimulation. Consistent with higher Th2 cytokine expression in Tim-3+ DSCs, treatment with Tim-3 released DSCs from LPS-induced inhibition of Th2 cytokine production. Blocking the Tim-3 signal with anti–Tim-3 mAb significantly down-regulated Th2 cytokine production by DSCs (Figure 5A). These data suggest that LPS stimulation results in declined Th2 cytokine production in addition to triggering apoptosis and pro-inflammatory reaction in DSCs. This may be another explanation for LPS induction of miscarriage.


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 promotes Th2 bias at the maternal-fetal interface.(A and B) Flow cytometric analysis of production of the indicated cytokines (A) and IRF4+ (B) by DSCs after stimulation with or without LPS (10 ng/ml) in the presence or absence of Tim-3 or anti-Tim-3 mAb. Data represent mean ± SEM. n = 10 DSCs in the first trimester of normal pregnancy. *P < 0.5, **P < 0.01, ***P < 0.001.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

f5: Tim-3 promotes Th2 bias at the maternal-fetal interface.(A and B) Flow cytometric analysis of production of the indicated cytokines (A) and IRF4+ (B) by DSCs after stimulation with or without LPS (10 ng/ml) in the presence or absence of Tim-3 or anti-Tim-3 mAb. Data represent mean ± SEM. n = 10 DSCs in the first trimester of normal pregnancy. *P < 0.5, **P < 0.01, ***P < 0.001.
Mentions: It has been reported that TLR-induced pregnancy loss can be prevented by maternal administration of the immuno-regulatory cytokine, IL-10321. Given that Tim-3 suppressed LPS-induced pro-inflammatory cytokine production and that Tim-3+ DSCs produced higher levels of Th2 cytokines than Tim-3− cells, we wondered whether Tim-3 affected Th2 cytokine production by DSCs upon LPS stimulation. Consistent with higher Th2 cytokine expression in Tim-3+ DSCs, treatment with Tim-3 released DSCs from LPS-induced inhibition of Th2 cytokine production. Blocking the Tim-3 signal with anti–Tim-3 mAb significantly down-regulated Th2 cytokine production by DSCs (Figure 5A). These data suggest that LPS stimulation results in declined Th2 cytokine production in addition to triggering apoptosis and pro-inflammatory reaction in DSCs. This may be another explanation for LPS induction of miscarriage.

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