TLR2 and TLR4 co-activation utilizes distinct signaling pathways for the production of Th1/Th2/Th17 cytokines in neonatal immune cells

•To delineate the signaling molecules involved in TLR co-activation in immune cells.•Phosphorylation of NFκB, ERK and Akt was found to be higher in co-stimulated cells.•Neonatal cells were more potent in the activation of ERK and Akt.•Neonatal cells activated NFκB similar to that of adult cells for...

Full description

Saved in:
Bibliographic Details
Published in:Cytokine (Philadelphia, Pa.) Pa.), 2016-09, Vol.85, p.191-200
Main Authors: Sugitharini, V., Shahana, P., Prema, A., Berla Thangam, E.
Format: Article
Language:English
Subjects:
Cell Line
Co-activation
Cytokines
Cytokines - metabolism
Humans
Infant, Newborn
Inflammation - metabolism
Inflammation Mediators - metabolism
Leukocytes, Mononuclear - metabolism
MAP Kinase Signaling System - physiology
Mast cells
Neonates
NF-kappa B - metabolism
Proto-Oncogene Proteins c-akt - metabolism
Signal Transduction - physiology
Signaling
Th1 Cells - metabolism
Th17 Cells - metabolism
Th2 Cells - metabolism
TLR
Toll-Like Receptor 2 - metabolism
Toll-Like Receptor 4 - metabolism
Citations: Items that this one cites
Items that cite this one
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary:•To delineate the signaling molecules involved in TLR co-activation in immune cells.•Phosphorylation of NFκB, ERK and Akt was found to be higher in co-stimulated cells.•Neonatal cells were more potent in the activation of ERK and Akt.•Neonatal cells activated NFκB similar to that of adult cells for IL-6 secretion.•Distinct signaling molecules were utilized for the production of different cytokines. Co-activation of TLR2 and TLR4 by gram negative and gram positive bacterial ligands induces a robust pro-inflammatory response in inflammatory cells. In order to understand the signaling mechanism, we aimed to delineate the signaling molecules involved in TLR2 and TLR4 co-activation in neonatal immune cells for the production of Th1/Th2/Th17 inflammatory cytokines. For this, we pretreated cord blood and peripheral blood mononuclear and human mast cells with specific signaling molecule inhibitors such as BAY117082, PD98059 and LY294002 and then stimulated with LPS and PGN and assayed for cytokines IL-6, IL-12/IL-23p40 (Th1), IL-13 (Th2), IL-23 (Th17) and RANTES secretion. We found that upon co-stimulation the phosphorylation of NFκBp65, ERK1/2 and Akt was found to be higher than when stimulated with individual ligands in CBMCs. Also, when compared to adult cells, neonatal cells were more potent in the activation of ERK and Akt through TLR2 and TLR4 co-activation. In addition, neonatal cells possess similar capacity to activate NFκB as that of adult cells for IL-6 secretion. Furthermore, all three signaling molecules were found to be involved in the production of Th17 cytokines which is detrimental during inflammation induced by infection in neonates whereas NFκB is mainly involved in the induction of pro-inflammatory response and Th2 cytokines production. In conclusion, different signaling molecules were utilized for the production of different cytokines in immune cells.
ISSN:1043-4666
1096-0023
DOI:10.1016/j.cyto.2016.06.024