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Microbiol Immunol. 2015 Oct;59(10):614-22. doi: 10.1111/1348-0421.12321.

Down-regulation of mitogen-activated protein kinases and nuclear factor-κB signaling is involved in rapamycin suppression of TLR2-induced inflammatory response in monocytic THP-1 cells.

Author information

1
Collaborative Innovation Center of Molecular Diagnosis and Laboratory Medicine in Henan Province, School of Laboratory Medicine, Xinxiang Medical University, Xinxiang, 453003.
2
Cancer Research Institute, Central South University, Key Laboratory of Carcinogenesis, National Health and Family Planning Commission, Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Changsha, 410078.
3
Third Affiliated Hospital, Xinxiang Medical University, Xinxiang, 453003, China.

Abstract

Tripalmitoyl-S-glycero-Cys-(Lys) 4 (Pam3CSK4) interacted with TLR2 induces inflammatory responses through the mitogen-activated protein kinases (MAPKs) and nuclear factor-κB (NF-κB) signal pathway. Rapamycin can suppress TLR-induced inflammatory responses; however, the detailed molecular mechanism is not fully understood. Here, the mechanism by which rapamycin suppresses TLR2-induced inflammatory responses was investigated. It was found that Pam3CSK4-induced pro-inflammatory cytokines were significantly down-regulated at both the mRNA and protein levels in THP-1 cells pre-treated with various concentrations of rapamycin. Inhibition of phosphatidylinositol 3-kinase/protein kinase-B (PI3K/AKT) signaling did not suppress the expression of pro-inflammatory cytokines, indicating that the immunosuppression mediated by rapamycin in THP1 cells is independent of the PI3K/AKT pathway. RT-PCR showed that Erk and NF-κB signal pathways are related to the production of pro-inflammatory cytokines. Inhibition of Erk or NF-κB signaling significantly down-regulated production of pro-inflammatory cytokines. Additionally, western blot showed that pre-treatment of THP-1 cells with rapamycin down-regulates MAPKs and NF-κB signaling induced by Pam3CSK4 stimulation, suggesting that rapamycin suppresses Pam3CSK4-induced pro-inflammatory cytokines via inhibition of TLR2 signaling. It was concluded that rapamycin suppresses TLR2-induced inflammatory responses by down-regulation of Erk and NF-κB signaling.

KEYWORDS:

MAPKs; Toll-like receptor 2; nuclear factor-κB; rapamycin

PMID:
26337526
DOI:
10.1111/1348-0421.12321
[Indexed for MEDLINE]
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