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

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Abstract

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.

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Abbreviations

ADAMs:

Desintegrin and metalloproteinases

ADAM-10:

Disintegrin and metalloproteinase (ADAM) 10

ADAM-17:

Desintegrin and metalloproteinase (ADAM) 17

Act:

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

ALT:

Alanine aminotransferase

AMPK:

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

AST:

Aspartate aminotransferase

BDNF:

Brain-derived neurotrophic factor

BLC:

Chemokine CXCL13

CCL4, CCL7, CCL14:

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

CPU:

Central processing unit

CX3CL1:

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

CX3CR1:

Chemokine CX3CL1 receptor 1

DMSO:

Dimethyl sulfoxide

ELISA:

Enzyme-linked immunosorbent assay

ENA-78:

Chemokine CXCL5

FGF-4:

Fibroblast growth factor 4

G-CSF:

Granulocyte colony-stimulating factor

GDM:

Gestational diabetes mellitus

GIT:

glucose impaired tolerance, prediabetes

GM-CSF:

Granulocyte-macrophage colony-stimulating factor

HG:

High glucose

HUVECs:

Human umbilical vein endothelial cells

IFN-γ :

Interferon gamma

IKK:

IκB kinase complex

IL:

Interleukin

initCX3CL1:

Initial concentrations of CX3CL1

initTNF-α :

Initial concentrations of TNF-α

IP-10:

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

JAK/STAT:

Janus kinase/signal transducers and activators of transcription

LPS:

Lipopolysaccharide

MCP-1-3:

Monocyte chemotactic proteins

MDC:

Macrophage-derived chemokine

MIP-1α, MIP-1β, MIP-1δ :

Macrophage inflammatory proteins 1: alpha, beta, delta

NF-κB:

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

NG:

Normal glucose

NIK:

NF-κB-inducing kinase

NK:

Natural killer cells

PARC:

Pulmonary and activation-regulated chemokine (chemokine CCL18)

PDGF:

Platelet-derived growth factor

PDK1:

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

PBS:

Phosphate-buffered saline

PI3-kinase:

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

pO2 :

Oxygen partial pressure

RANTES:

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

SCF:

Stem cell factor

TARC:

Thymus- and activation-regulated chemokine (chemokine CCL17)

TGF-β :

Transforming growth factor β

TIMP-1-2:

Tissue inhibitors of metalloproteinases

TNFRSF1A:

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

TNF-α, TNF-β :

Tumor necrosis factors: alpha, beta

TPO:

Thyroid peroxidase

VEGF:

Vascular endothelial growth factor

V/EVTI:

Vascular/extravascular tissular index

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Acknowledgements

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

Funding

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.

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Authors and Affiliations

  1. Department of General & Experimental Pathology with Centre for Preclinical Research and Technology (CEPT), Medical University of Warsaw, Pawinskiego 3C, 02-106, Warsaw, Poland

    D. Szukiewicz, Grzegorz Szewczyk, Michal Pyzlak & Aleksandra Stangret

  2. Department of Obstetrics & Gynecology, Second Faculty of Medicine, Medical University of Warsaw, Kondratowicza 8, 03-242, Warsaw, Poland

    Michal Bachanek, Seweryn Trojanowski & Habib Alkhalayla

  3. Department of Pathology, Professor Witold Orlowski Public Clinical Hospital, Medical Center for Postgraduate Education, Czerniakowska 231, 00-416, Warsaw, Poland

    Jaroslaw Wejman

Authors
  1. D. Szukiewicz
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  2. Grzegorz Szewczyk
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  3. Michal Pyzlak
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  4. Aleksandra Stangret
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  5. Michal Bachanek
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  6. Seweryn Trojanowski
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  7. Habib Alkhalayla
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  8. Jaroslaw Wejman
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Corresponding author

Correspondence to D. Szukiewicz.

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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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Szukiewicz, D., Szewczyk, G., Pyzlak, M. et al. Anti-inflammatory Action of Metformin with Respect to CX3CL1/CX3CR1 Signaling in Human Placental Circulation in Normal-Glucose Versus High-Glucose Environments. Inflammation 41, 2246–2264 (2018). https://doi.org/10.1007/s10753-018-0867-7

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  • DOI: https://doi.org/10.1007/s10753-018-0867-7

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