PlGF enhances TLR-dependent inflammatory responses in human mononuclear phagocytes

Laura F. Newell, Shernan G. Holtan, Jane E. Yates, Leonardo Pereira, Jeffrey W. Tyner, Irina Burd, Grover C. Bagby

Research output: Contribution to journalArticle

Abstract

Problem: Levels of placental growth factor (PlGF) peak during third trimester of pregnancy, a time when women are at increased risk of virus-induced morbidity. We hypothesized PlGF might contribute to an exaggerated inflammatory response to Toll-like receptor (TLR) activation. Method of study: Primary human adult and cord blood CD14+ cells were cultured in the presence of TLR ligands and/or PlGF. Results: PlGF significantly enhanced the magnitude and duration of TNF messenger RNA and protein production by TLR-7/8-activated monocytes, and increased subsequent production of TNF-independent inflammatory cytokines. This PlGF/TLR effect involved multiple inflammatory cytokines/chemokines and was seen with the majority of TLR agonists. PlGF enhanced phosphorylation of IkappaB kinase (IKK) in monocytes stimulated with the TLR-7/8 agonist R848, and IKK inhibition completely suppressed the PlGF effect. Conclusion: PlGF enhances TLR-signaling upstream of IKK and contributes to an exaggerated pathologic pro-inflammatory state in response to activation of maternal and fetal mononuclear phagocytes by specific TLR agonists.

Original languageEnglish (US)
JournalAmerican Journal of Reproductive Immunology
DOIs
StateAccepted/In press - 2017

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Toll-Like Receptors
Phagocytes
Intercellular Signaling Peptides and Proteins
I-kappa B Kinase
Toll-Like Receptor 8
Toll-Like Receptor 7
Monocytes
resiquimod
Cytokines
Third Pregnancy Trimester
Fetal Blood
Chemokines
Blood Cells
Phosphorylation
Mothers
Ligands
Viruses
Morbidity
Messenger RNA

Keywords

  • Innate immunity
  • Mononuclear phagocytes
  • Placental growth factor
  • Pregnancy
  • Toll-like receptors
  • Viral infections

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology
  • Reproductive Medicine
  • Obstetrics and Gynecology

Cite this

PlGF enhances TLR-dependent inflammatory responses in human mononuclear phagocytes. / Newell, Laura F.; Holtan, Shernan G.; Yates, Jane E.; Pereira, Leonardo; Tyner, Jeffrey W.; Burd, Irina; Bagby, Grover C.

In: American Journal of Reproductive Immunology, 2017.

Research output: Contribution to journalArticle

Newell, Laura F. ; Holtan, Shernan G. ; Yates, Jane E. ; Pereira, Leonardo ; Tyner, Jeffrey W. ; Burd, Irina ; Bagby, Grover C. / PlGF enhances TLR-dependent inflammatory responses in human mononuclear phagocytes. In: American Journal of Reproductive Immunology. 2017.
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abstract = "Problem: Levels of placental growth factor (PlGF) peak during third trimester of pregnancy, a time when women are at increased risk of virus-induced morbidity. We hypothesized PlGF might contribute to an exaggerated inflammatory response to Toll-like receptor (TLR) activation. Method of study: Primary human adult and cord blood CD14+ cells were cultured in the presence of TLR ligands and/or PlGF. Results: PlGF significantly enhanced the magnitude and duration of TNF messenger RNA and protein production by TLR-7/8-activated monocytes, and increased subsequent production of TNF-independent inflammatory cytokines. This PlGF/TLR effect involved multiple inflammatory cytokines/chemokines and was seen with the majority of TLR agonists. PlGF enhanced phosphorylation of IkappaB kinase (IKK) in monocytes stimulated with the TLR-7/8 agonist R848, and IKK inhibition completely suppressed the PlGF effect. Conclusion: PlGF enhances TLR-signaling upstream of IKK and contributes to an exaggerated pathologic pro-inflammatory state in response to activation of maternal and fetal mononuclear phagocytes by specific TLR agonists.",
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AU - Newell, Laura F.

AU - Holtan, Shernan G.

AU - Yates, Jane E.

AU - Pereira, Leonardo

AU - Tyner, Jeffrey W.

AU - Burd, Irina

AU - Bagby, Grover C.

PY - 2017

Y1 - 2017

N2 - Problem: Levels of placental growth factor (PlGF) peak during third trimester of pregnancy, a time when women are at increased risk of virus-induced morbidity. We hypothesized PlGF might contribute to an exaggerated inflammatory response to Toll-like receptor (TLR) activation. Method of study: Primary human adult and cord blood CD14+ cells were cultured in the presence of TLR ligands and/or PlGF. Results: PlGF significantly enhanced the magnitude and duration of TNF messenger RNA and protein production by TLR-7/8-activated monocytes, and increased subsequent production of TNF-independent inflammatory cytokines. This PlGF/TLR effect involved multiple inflammatory cytokines/chemokines and was seen with the majority of TLR agonists. PlGF enhanced phosphorylation of IkappaB kinase (IKK) in monocytes stimulated with the TLR-7/8 agonist R848, and IKK inhibition completely suppressed the PlGF effect. Conclusion: PlGF enhances TLR-signaling upstream of IKK and contributes to an exaggerated pathologic pro-inflammatory state in response to activation of maternal and fetal mononuclear phagocytes by specific TLR agonists.

AB - Problem: Levels of placental growth factor (PlGF) peak during third trimester of pregnancy, a time when women are at increased risk of virus-induced morbidity. We hypothesized PlGF might contribute to an exaggerated inflammatory response to Toll-like receptor (TLR) activation. Method of study: Primary human adult and cord blood CD14+ cells were cultured in the presence of TLR ligands and/or PlGF. Results: PlGF significantly enhanced the magnitude and duration of TNF messenger RNA and protein production by TLR-7/8-activated monocytes, and increased subsequent production of TNF-independent inflammatory cytokines. This PlGF/TLR effect involved multiple inflammatory cytokines/chemokines and was seen with the majority of TLR agonists. PlGF enhanced phosphorylation of IkappaB kinase (IKK) in monocytes stimulated with the TLR-7/8 agonist R848, and IKK inhibition completely suppressed the PlGF effect. Conclusion: PlGF enhances TLR-signaling upstream of IKK and contributes to an exaggerated pathologic pro-inflammatory state in response to activation of maternal and fetal mononuclear phagocytes by specific TLR agonists.

KW - Innate immunity

KW - Mononuclear phagocytes

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KW - Pregnancy

KW - Toll-like receptors

KW - Viral infections

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