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|標題:||Tilapia Hepcidin 2-3 Peptide Modulates Lipopolysaccharide-induced Cytokines and Inhibits Tumor Necrosis Factor-alpha through Cyclooxygenase-2 and Phosphodiesterase 4D||作者:||Rajanbabu, V.
|關鍵字:||nf-kappa-b;nitric-oxide synthase;raw 264.7 macrophages;protein-kinase;inflammatory cytokines;antimicrobial peptide;transcription factor;negative regulator;immune-response;innate;immunity||Project:||Journal of Biological Chemistry||期刊/報告no：:||Journal of Biological Chemistry, Volume 285, Issue 40, Page(s) 30577-30586.||摘要:||
The antimicrobial peptide, tilapia hepcidin (TH) 2-3, belongs to the hepcidin family, and its antibacterial function has been reported. Here, we examined the TH2-3-mediated regulation of proinflammatory cytokines in bacterial endotoxin lipopolysaccharide (LPS)-stimulated mouse macrophages. The presence of TH2-3 in LPS-stimulated cells reduced the amount of tumor necrosis factor (TNF)-alpha secretion. From a microarray, real-time polymerase chain reaction (PCR), and cytokine array studies, we showed down-regulation of the proinflammatory cytokines TNF-alpha, interleukin (IL)-1 alpha, IL-1 beta, IL-6, and the prostaglandin synthesis gene, cyclooxygenase (COX)-2, by TH2-3. Studies with the COX-2-specific inhibitor, melaxicam, and with COX-2-overexpressing cells demonstrated the positive regulation of TNF-alpha and negative regulation of cAMP degradation-specific phosphodiesterase (PDE) 4D by COX-2. In LPS-stimulated cells, TH2-3 acts like melaxicam and down-regulates COX-2 and up-regulates PDE4D. The reduction in intracellular cAMP by TH2-3 or melaxicam in LPS-stimulated cells supports the negative regulation of PDE4D by COX-2 and TH2-3. This demonstrates that the inhibition of COX-2 is among the mechanisms through which TH2-3 controls TNF-alpha release. At 1 h after treatment, the presence of TH2-3 in LPS-stimulated cells had suppressed the induction of pERK1/2 and prevented the LPS-stimulated nuclear accumulation of NF-kappa B family proteins of p65, NF-kappa B2, and c-Rel. In conclusion, TH2-3 inhibits TNF-alpha and other proinflammatory cytokines through COX-2-, PDE4D-, and pERK1/2-dependent mechanisms.
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