, Volume 41, Issue 6, pp 2246–2264 | Cite as

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

  • D. SzukiewiczEmail author
  • Grzegorz Szewczyk
  • Michal Pyzlak
  • Aleksandra Stangret
  • Michal Bachanek
  • Seweryn Trojanowski
  • Habib Alkhalayla
  • Jaroslaw Wejman


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.


metformin chemokine CX3CL1 fractalkine human placenta high-glucose environment fractalkine receptor 



Desintegrin and metalloproteinases


Disintegrin and metalloproteinase (ADAM) 10


Desintegrin and metalloproteinase (ADAM) 17


Serine/threonine kinase Akt (protein kinase B, PKB)


Alanine aminotransferase


Adenosine 5’- monophosphate(AMP)-activated protein kinase


Aspartate aminotransferase


Brain-derived neurotrophic factor


Chemokine CXCL13


C-C motif chemokines: ligand 4, 7, and 14, respectively


Central processing unit


C-X3-C motif chemokine ligand 1(fractalkine, neurotactin)


Chemokine CX3CL1 receptor 1


Dimethyl sulfoxide


Enzyme-linked immunosorbent assay


Chemokine CXCL5


Fibroblast growth factor 4


Granulocyte colony-stimulating factor


Gestational diabetes mellitus


glucose impaired tolerance, prediabetes


Granulocyte-macrophage colony-stimulating factor


High glucose


Human umbilical vein endothelial cells


Interferon gamma


IκB kinase complex




Initial concentrations of CX3CL1


Initial concentrations of TNF-α


Chemokine CXCL10 (interferon gamma-induced protein 10; small inducible cytokine B10)


Janus kinase/signal transducers and activators of transcription




Monocyte chemotactic proteins


Macrophage-derived chemokine

MIP-1α, MIP-1β, MIP-1δ

Macrophage inflammatory proteins 1: alpha, beta, delta


Nuclear factor kappa-light-chain-enhancer of activated B cells


Normal glucose


NF-κB-inducing kinase


Natural killer cells


Pulmonary and activation-regulated chemokine (chemokine CCL18)


Platelet-derived growth factor


Pyruvate dehydrogenase kinase 1 (pyruvate dehydrogenase [acetyl-transferring] kinase isozyme 1)


Phosphate-buffered saline


Phosphoinositide 3-kinase (phosphatidylinositol-4,5-bisphosphate 3-kinase)


Oxygen partial pressure


Regulated on activation, normal T-cell expressed and secreted (chemokine CCL5)


Stem cell factor


Thymus- and activation-regulated chemokine (chemokine CCL17)


Transforming growth factor β


Tissue inhibitors of metalloproteinases


Tumor necrosis factor receptor superfamily member 1A (tumor necrosis factor receptor 1; CD120a)

TNF-α, TNF-β

Tumor necrosis factors: alpha, beta


Thyroid peroxidase


Vascular endothelial growth factor


Vascular/extravascular tissular index



The creative contribution to the study design provided by Professor Slawomir Maslinski is gratefully acknowledged.


This study was funded by internal Grant no. 2M2/W1/16, funded by the Medical University of Warsaw, Poland. No additional external funding was received for this study.

Compliance with Ethical Standards

Conflict of Interest

The authors declare that they have no conflict of interest.

Ethical Approval

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.

Informed Consent

Informed consent was obtained from all individual participants included in the study.


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Authors and Affiliations

  1. 1.Department of General & Experimental Pathology with Centre for Preclinical Research and Technology (CEPT)Medical University of WarsawWarsawPoland
  2. 2.Department of Obstetrics & Gynecology, Second Faculty of MedicineMedical University of WarsawWarsawPoland
  3. 3.Department of PathologyProfessor Witold Orlowski Public Clinical Hospital, Medical Center for Postgraduate EducationWarsawPoland

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