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Inflammation

, 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. Szukiewicz
  • Grzegorz Szewczyk
  • Michal Pyzlak
  • Aleksandra Stangret
  • Michal Bachanek
  • Seweryn Trojanowski
  • Habib Alkhalayla
  • Jaroslaw Wejman
ORIGINAL ARTICLE
  • 100 Downloads

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.

KEY WORDS

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

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

Notes

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.

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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© Springer Science+Business Media, LLC, part of Springer Nature 2018

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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