Anti-inflammatory Action of Metformin with Respect to CX3CL1/CX3CR1 Signaling in Human Placental Circulation in Normal-Glucose Versus High-Glucose Environments

Upregulation of chemokine CX3CL1 and its receptor CX3CR1 occurs in the diabetic human placenta. Metformin, an insulin-sensitizing biguanide, is used in the therapy of diabetic pregnancy. By preventing the activation of NF-κB, metformin exhibits anti-inflammatory properties. We examined the influence...

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Bibliographic Details
Published in:Inflammation 2018-12, Vol.41 (6), p.2246-2264
Main Authors: Szukiewicz, D., Szewczyk, Grzegorz, Pyzlak, Michal, Stangret, Aleksandra, Bachanek, Michal, Trojanowski, Seweryn, Alkhalayla, Habib, Wejman, Jaroslaw
Format: Article
Language:English
Subjects:
Adult
Animals
Anti-inflammatory agents
Anti-Inflammatory Agents - pharmacology
Antidiabetics
Biomedical and Life Sciences
Biomedicine
Blood Glucose
Chemokine CX3CL1 - metabolism
CX3C Chemokine Receptor 1 - metabolism
CX3CR1 protein
Diabetes
Diabetes mellitus
Female
Glucose
Humans
Hyperglycemia
Hypoglycemic Agents - pharmacology
Immunology
Inflammation
Insulin
Internal Medicine
Lysates
Metformin
Metformin - pharmacokinetics
NF-kappa B - drug effects
NF-kappa B - metabolism
NF-κB protein
Original Article
Pathology
Perfusion
Pharmacology/Toxicology
Placenta
Placental Circulation - drug effects
Pregnancy
Receptors, Tumor Necrosis Factor, Type I - drug effects
Receptors, Tumor Necrosis Factor, Type I - metabolism
Rheumatology
Signal Transduction - drug effects
Tumor necrosis factor receptors
Tumor Necrosis Factor-alpha - metabolism
Tumor necrosis factor-α
Young Adult
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Summary:Upregulation of chemokine CX3CL1 and its receptor CX3CR1 occurs in the diabetic human placenta. Metformin, an insulin-sensitizing biguanide, is used in the therapy of diabetic pregnancy. By preventing the activation of NF-κB, metformin exhibits anti-inflammatory properties. We examined the influence of hyperglycemia (25 mmol/L glucose; HG group; N  = 36) on metformin-mediated effects on CX3CL1 and TNF-α production by placental lobules perfused extracorporeally. Additionally, CX3CR1 expression and contents of CX3CR1, TNF-α receptor 1 (TNFR1), and NF-κB proteins in the placental tissue were evaluated. Placentae perfused under normoglycemia (5 mmol/L glucose; NG group; N  = 36) served as the control. Metformin (2.5 and 5.0 mg/L; subgroups B and C) lowered the production of CX3CL1 and TNF-α in a dose-dependent and time-dependent manner. Hyperglycemia did not weaken the strength of these metformin effects. Moreover, CX3CL1 levels after perfusion with 5.0 mg/L metformin were reduced by 33.28 and 33.83% (at 120 and 150 min, respectively) in the HG-C subgroup versus 24.98 and 23.66% in the NG-C subgroup, which indicated an augmentation of the metformin action over time in hyperglycemia. CX3CR1 expression was significantly higher in the HG-B and HG-C subgroups compared to that in the NG-B and NG-C subgroups. Increased CX3CR1 protein content in the placental lysates was observed in subgroups B and C. The two higher metformin concentrations significantly decreased the levels of NF-κBp65 protein content in both groups. However, the decrease was significantly stronger in hyperglycemia. TNFR1 upregulation in the HG group was not affected by metformin. Further studies on metformin therapy during pregnancy are needed, including safety issues.
ISSN:0360-3997
1573-2576
DOI:10.1007/s10753-018-0867-7