Molecular mechanisms of the secretion of cytokines and chemokines from human monocytes activated by pneumococcal surface protein A (PspA): Roles of mitogen-activated protein kinases and NF-kappaB.
Pneumococcal surface protein A (PspA) plays a key role in the pathogenesis of invasive pneumococcal infection. PspA might modulate specific immune responses in human population. Circulating monocytes are essential for the innate responses and subsequent acquired immune responses to Streptococcus pneumoniae. In this study, we investigated the effects of PspA on cytokine and chemokine secretion from human peripheral blood monocytes and the underlying intracellular signaling mechanisms. Stimulation of monocytes with purified PspA protein induced the significant release of inflammatory cytokine IL-6 and chemokines including CXCL8, CCL2, CCL4 and CCL5. Products from PspA-deficient mutant pneumococcus that did not express PspA induced significantly less secretion of these mediators than those from wild type pneumococcus. Further investigations showed that PspA activated the extracellular signal-regulated kinase (ERK), c-Jun N-terminal kinase (JNK), p38 mitogen activated protein kinase (MAPK) and nuclear factor (NF)-kappaB signaling pathways in human monocytes. Moreover, inhibition of these pathways using selective inhibitors could significantly reduce the cytokine and chemokine secretion induced by PspA. Taken together, our findings provide insight for PspA-mediated activation of human monocytes via NF-kappaB and MAPKs signaling cascades in the pathogenesis of invasive pneumococcal infection.
Cao
Ju
J
Department of Laboratory Medicine, West China Hospital, Sichuan University, Chengdu 610041, China. doccjhx@163.com
Chen
Tingmei
T
Gong
Yi
Y
Ying
Bingwu
B
Li
Dairong
D
Xu
Wenchun
W
Zhang
Xuemei
X
Wang
Lanlan
L
Yin
Yibing
Y
D001426:Bacterial Proteins / Q000276:immunology*; D002478:Cells, Cultured; D018925:Chemokines / Q000378:metabolism*; D016207:Cytokines / Q000378:metabolism*; D006801:Humans; D007249:Inflammation / Q000378:metabolism; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D009000:Monocytes / Q000276:immunology* / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism*; D015398:Signal Transduction
D001426:Bacterial Proteins; D018925:Chemokines; D016207:Cytokines; D016328:NF-kappa B; C051592:pneumococcal surface protein A; D020928:Mitogen-Activated Protein Kinases