Suppressing LPS-induced early signal transduction in macrophages by a polyphenol degradation product: a critical role of MKP-1.
Macrophages represent the first defense line against bacterial infection and therefore, play a crucial role in early inflammatory response. In this study, we investigated the role of MAPKs and MKP-1 activation in regulation of an early inflammatory response in RAW 264.7 macrophage cells. We induced the inflammatory response by treating the macrophages with LPS and inhibited an early inflammatory response by using ferulaldehyde, a water-soluble end-product of dietary polyphenol degradation that we found previously to exert its beneficial anti-inflammatory effects during the early phase of in vivo inflammation. We found that LPS-induced ROS and nitrogen species formations were reduced by ferulaldehyde in a concentration-dependent manner, and ferulaldehyde protected mitochondria against LPS-induced rapid and massive membrane depolarization. LPS induced early suppression of MKP-1, which was accompanied by activation of JNK, ERK, and p38 MAPK. By reversing LPS-induced early suppression of MKP-1, ferulaldehyde diminished MAPK activation, thereby inhibiting NF-κB activation, mitochondrial depolarization, and ROS production. Taken together, our data suggest that ferulaldehyde exerts its early anti-inflammatory effect by preserving the mitochondrial membrane integrity and shifting the expression of MKP-1 forward in time in macrophages.
Tucsek
Zsuzsanna
Z
Department of Biochemistry and Medical Chemistry, Faculty of Medicine, University of Pecs, Pecs, H-7624, Hungary.
Radnai
Balazs
B
Racz
Boglarka
B
Debreceni
Balazs
B
Priber
Janos K
JK
Dolowschiak
Tamas
T
Palkovics
Tamas
T
Gallyas
Ferenc
F
Sumegi
Balazs
B
Veres
Balazs
B
D000447:Aldehydes / Q000494:pharmacology*; D000818:Animals; D002460:Cell Line; D054638:Dual Specificity Phosphatase 1 / Q000235:genetics / Q000378:metabolism*; D004789:Enzyme Activation / Q000187:drug effects; D005419:Flavonoids / Q000494:pharmacology*; D005434:Flow Cytometry; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D008070:Lipopolysaccharides / Q000494:pharmacology*; D008264:Macrophages / Q000187:drug effects* / Q000201:enzymology*; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D051379:Mice; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D009585:Nitrogen Dioxide / Q000378:metabolism; D010636:Phenols / Q000494:pharmacology*; D010766:Phosphorylation / Q000187:drug effects; D059808:Polyphenols; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*
D000447:Aldehydes; D005419:Flavonoids; D008070:Lipopolysaccharides; D016328:NF-kappa B; D010636:Phenols; D059808:Polyphenols; D012333:RNA, Messenger; D017382:Reactive Oxygen Species; D020928:Mitogen-Activated Protein Kinases; D054638:Dual Specificity Phosphatase 1; C517020:Dusp1 protein, mouse; D009585:Nitrogen Dioxide