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PlGF enhances TLR-dependent inflammatory responses in human mononuclear phagocytes
Laura F Newell1, Shernan G Holtan2, Jane E Yates3
1Hematology and Medical Oncology, Oregon Health & Science University, Knight Cancer Institute, Portland, OR, USA.
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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