Objectives: Preeclampsia (PE) is a severe pregnancy-related syndrome characterized by exacerbated placental inflammation. LMWH is widely used during PE since several trials described its anti-inflammatory effect. Nevertheless, LMWH mechanisms of action on the placental tissue are still unclear. HMGB1 is a transcription factor with an extracellular cytokine-like function able to induce pro-inflammatory TNFα and IL-6 molecules. LMWH binds to HMGB1 in-vitro, thus changing its structural conformation and inhibiting its activity. Since HMGB1 has been previously found up-regulated in PE, in the present study we investigated LMWH's modulation of HMGB1 and its targets TNFα and IL-6 in the placental tissue. Methods: Twenty-eight normal placental villous explants were treated for 48h with different concentrations of LMWH (Parnaparin 50U, 5U, 0.5U). HMGB1, TNFα and IL-6 mRNA expression was assessed by Real Time PCR while HMGB1 protein expression was analyzed by Western Blot analysis. Results: While 50U and 5U were toxic for our in-vitro model, we reported significantly decreased gene expression levels of HMGB1, TNFα and IL-6 in placental villous explants treated with LMWH 0.5U vs untreated controls. In contrast, HMGB1 protein levels were increased in LMWH 0.5U explants compared to controls. Conclusion: Herein, we described a direct effect of LMWH on placental HMGB1 modulation. Indeed, HMGB1 protein increase accompanied by decreased TNFα and IL-6 expression in LMWH villous explants confirm the anti-inflammatory effect of heparin and suggest that it is mediated by structural modifications of HMGB1 able to promote its accumulation and to inhibit its function. Further investigations are required.
Anti-inflammatory effect of Low Molecular Weight Heparin (LMWH) is mediated by Placental High Mobility Group Box 1 (HMGB1) Modulation: New Therapeutic Perspectives for Preeclampsia
NUZZO, ANNA MARIA;TODROS, Tullia;ROLFO, Alessandro
2013-01-01
Abstract
Objectives: Preeclampsia (PE) is a severe pregnancy-related syndrome characterized by exacerbated placental inflammation. LMWH is widely used during PE since several trials described its anti-inflammatory effect. Nevertheless, LMWH mechanisms of action on the placental tissue are still unclear. HMGB1 is a transcription factor with an extracellular cytokine-like function able to induce pro-inflammatory TNFα and IL-6 molecules. LMWH binds to HMGB1 in-vitro, thus changing its structural conformation and inhibiting its activity. Since HMGB1 has been previously found up-regulated in PE, in the present study we investigated LMWH's modulation of HMGB1 and its targets TNFα and IL-6 in the placental tissue. Methods: Twenty-eight normal placental villous explants were treated for 48h with different concentrations of LMWH (Parnaparin 50U, 5U, 0.5U). HMGB1, TNFα and IL-6 mRNA expression was assessed by Real Time PCR while HMGB1 protein expression was analyzed by Western Blot analysis. Results: While 50U and 5U were toxic for our in-vitro model, we reported significantly decreased gene expression levels of HMGB1, TNFα and IL-6 in placental villous explants treated with LMWH 0.5U vs untreated controls. In contrast, HMGB1 protein levels were increased in LMWH 0.5U explants compared to controls. Conclusion: Herein, we described a direct effect of LMWH on placental HMGB1 modulation. Indeed, HMGB1 protein increase accompanied by decreased TNFα and IL-6 expression in LMWH villous explants confirm the anti-inflammatory effect of heparin and suggest that it is mediated by structural modifications of HMGB1 able to promote its accumulation and to inhibit its function. Further investigations are required.
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