期刊
JOURNAL OF INNATE IMMUNITY
卷 7, 期 4, 页码 428-440出版社
KARGER
DOI: 10.1159/000371517
关键词
Lipopolysaccharide; microRNA; Peptidoglycan; Toll-like receptor ligands
类别
资金
- Lupus Research Institute
- National Institutes of Health [AI47859]
- Andrew J. Semesco Foundation, Ocala, Fla., USA
- NIAMS Rheumatology training grant [T32 AR007603]
- NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASES [R01AI047859, R21AI047859] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE OF ARTHRITIS AND MUSCULOSKELETAL AND SKIN DISEASES [T32AR007603] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE OF ENVIRONMENTAL HEALTH SCIENCES [R01ES021464] Funding Source: NIH RePORTER
Unwarranted overproduction of cytokines, such as interleukin (IL)-1 beta, can cause moderate to severe pathological complications, and thus elaborate mechanisms are needed to regulate its onset and termination. One such, well-known, mechanism is endotoxin tolerance, generally described as controlling lipopolysaccharide Toll-like receptor 4 (LPS-TLR4) signaling. Similarly, cytokine-induced tolerance plays an important role in regulating an overactive cytokine response. In this report, the capability of IL-1 beta to induce tolerance and cross-tolerance to various inflammatory ligands was investigated. IL-1 beta-stimulated THP-1 monocytes showed a gradual increase of microRNA (miR)-146a, reaching 15-fold expression by 24 h. miR-146a upregulation induced tolerance toward subsequent challenges of IL-1 beta, LPS, peptidoglycan, Pam and flagellin in THP-1 cells. The induction of tolerance was dependent on the IL-1 beta priming dose and associated increase of miR-146a expression. Moreover, IL-1 beta-treated THP-1 cells showed sustained miR-146a upregulation that repressed IRAK1 and TRAF6 adaptor molecules. Transfection of miR-146a alone mimicked IL-1 beta-induced tolerance in monocytes, while cells transfected with miR-146a inhibitor increased chemokine production. A comparable cytokine response regulated by miR-146a was also detected in lung epithelial A549 cells, purified human monocytes and mouse peritoneal macrophages. Thus, our studies showed that miR-146a was crucial for monocytic cell-based IL-1 beta tolerance and cross-tolerance, and thus opens the way for future research in the development of therapeutics for inflammatory diseases. (C) 2015 S. Karger AG, Basel
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