Résumé
Serum amyloid A (SAA) has been regarded as an important mediator of inflammatory responses. The effect of several formyl peptide receptor-like 1 (FPRL1) ligands on the production of IL-8 by SAA was investigated in human neutrophils. Among the ligands tested, LL-37 was found to specifically inhibit SAA-induced IL-8 production in transcriptional and post-transcriptional levels. Since SAA stimulated IL-8 production via ERK and p38 MAPK in human neutrophils, we tested the effect of LL-37 on SAA induction for these two MAPKs. LL-37 caused a dramatic inhibition of ERK and p38 MAPK activity, which is induced by SAA. LL-37 was also found to inhibit SAA-stimulated neutrophil chemotactic migration. Further, the LL-37-induced inhibitory effect was mediated by FPRL1. Our findings indicate that LL-37 is expected to be useful in the inhibition of SAA signaling and for the development of drugs against SAA-related inflammatory diseases.
Sujets)
Animaux , Humains , Rats , Peptides antimicrobiens cationiques/pharmacologie , Lignée cellulaire tumorale , Mouvement cellulaire , Chimiotaxie des leucocytes , Interleukine-8/biosynthèse , MAP Kinase Kinase Kinases/métabolisme , Granulocytes neutrophiles/effets des médicaments et des substances chimiques , Protéines proto-oncogènes/métabolisme , Récepteurs aux peptides formylés/métabolisme , Récepteurs de la lipoxine/métabolisme , Protéine amyloïde A sérique/antagonistes et inhibiteurs , Transduction du signal , Transcription génétiqueRésumé
Serum amyloid A (SAA) has been regarded as an important mediator of inflammatory responses. The effect of several formyl peptide receptor-like 1 (FPRL1) ligands on the production of IL-8 by SAA was investigated in human neutrophils. Among the ligands tested, LL-37 was found to specifically inhibit SAA-induced IL-8 production in transcriptional and post-transcriptional levels. Since SAA stimulated IL-8 production via ERK and p38 MAPK in human neutrophils, we tested the effect of LL-37 on SAA induction for these two MAPKs. LL-37 caused a dramatic inhibition of ERK and p38 MAPK activity, which is induced by SAA. LL-37 was also found to inhibit SAA-stimulated neutrophil chemotactic migration. Further, the LL-37-induced inhibitory effect was mediated by FPRL1. Our findings indicate that LL-37 is expected to be useful in the inhibition of SAA signaling and for the development of drugs against SAA-related inflammatory diseases.
Sujets)
Animaux , Humains , Rats , Peptides antimicrobiens cationiques/pharmacologie , Lignée cellulaire tumorale , Mouvement cellulaire , Chimiotaxie des leucocytes , Interleukine-8/biosynthèse , MAP Kinase Kinase Kinases/métabolisme , Granulocytes neutrophiles/effets des médicaments et des substances chimiques , Protéines proto-oncogènes/métabolisme , Récepteurs aux peptides formylés/métabolisme , Récepteurs de la lipoxine/métabolisme , Protéine amyloïde A sérique/antagonistes et inhibiteurs , Transduction du signal , Transcription génétiqueRésumé
In this study, we observed that lysophosphatidylglycerol (LPG) completely inhibited a formyl peptide receptor like-1 (FPRL1) agonist (MMK-1)-stimulated chemotactic migration in human phagocytes, such as neutrophils and monocytes. LPG also dramatically inhibited IL-1beta production by another FPRL1 agonist serum amyloid A (SAA) in human phagocytes. However, LPG itself induced intracellular calcium increase and superoxide anion production in human phagocytes. Keeping in mind that phagocytes migration and IL-1beta production by FPRL1 are important for the induction of inflammatory response, our data suggest that LPG can be regarded as a useful material for the modulation of inflammatory response induced by FPRL1 activation.