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

• Published in: Inflammation Vol. 41; no. 6; pp. 2246 - 2264
• Main Authors: Szukiewicz, D., Szewczyk, Grzegorz, Pyzlak, Michal, Stangret, Aleksandra, Bachanek, Michal, Trojanowski, Seweryn, Alkhalayla, Habib, Wejman, Jaroslaw
• Format: Journal Article
• Language: English
• Published: New York Springer US 01-12-2018; Springer Nature B.V
• 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; high-glucose environment; metformin; fractalkine; fractalkine receptor; chemokine CX3CL1; human placenta
• ISSN: 0360-3997; 1573-2576
• DOI: 10.1007/s10753-018-0867-7

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;
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 = 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.