Nerve growth factor promotes TLR4 signaling-induced maturation of human dendritic cells in vitro through inducible p75NTR 1.
Nerve growth factor (NGF) has been shown to play important roles in the differentiation, function, and survival of immune cells, contributing to immune responses and pathogenesis of autoimmune diseases. Dendritic cells (DCs) are a potent initiator for immune and inflammatory responses upon recognition of pathogens via Toll-like receptors (TLR). However, expression of NGF and its receptors on human monocyte-derived DCs (MoDCs) and the role of NGF in the response of DCs to TLR ligands remain to be investigated. In the present study, we demonstrate that there were weak expressions of NGF and no expression of NGF receptors p140(TrkA) and p75(NTR) on human immature MoDCs, however, the expression of NGF and p75(NTR) on MoDCs could be significantly up-regulated by LPS in a dose- and time-dependent manner. NGF could markedly promote LPS-induced expression of HLA-DR, CD40, CD80, CD83, CD86, CCR7, secretion of IL-12p40 and proinflammatory cytokines IL-1, IL-6, TNF-alpha, and the T cell-stimulating capacity of MoDCs, indicating that NGF can promote LPS-induced DC maturation. The promoting effect of NGF on LPS-induced MoDCs maturation could be completely abolished by pretreatment of MoDCs with p75(NTR) antagonist, suggesting that LPS-induced p75(NTR) mediates the effect. Furthermore, increased activation of the p38MAPK and NF-kappaB pathways has been shown to be responsible for the NGF-promoted DC maturation. Therefore, NGF facilitates TLR4 signaling-induced maturation of human DCs through LPS-up-regulated p75(NTR) via activation of p38 MAPK and NF-kappaB pathways, providing another mechanism for the involvement of NGF in the immune responses and pathogenesis of autoimmune diseases.
Jiang
Yingming
Y
Institute of Immunology and National Key Laboratory of Medical Immunology, Second Military Medical University, Shanghai, People's Republic of China.
Chen
Guoyou
G
Zhang
Yi
Y
Lu
Lin
L
Liu
Shuxun
S
Cao
Xuetao
X
D002454:Cell Differentiation / Q000187:drug effects*; D016207:Cytokines / Q000378:metabolism; D003713:Dendritic Cells / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism*; D005786:Gene Expression Regulation; D006801:Humans; D008024:Ligands; D008070:Lipopolysaccharides / Q000494:pharmacology; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D009414:Nerve Growth Factors / Q000494:pharmacology*; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D010641:Phenotype; D017475:Receptors, Nerve Growth Factor / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects*; D013997:Time Factors; D051197:Toll-Like Receptor 4 / Q000378:metabolism*
D016207:Cytokines; D008024:Ligands; D008070:Lipopolysaccharides; D016328:NF-kappa B; C484065:NGFR protein, human; D009414:Nerve Growth Factors; D009419:Nerve Tissue Proteins; D017475:Receptors, Nerve Growth Factor; C495345:TLR4 protein, human; D051197:Toll-Like Receptor 4; D020928:Mitogen-Activated Protein Kinases