Abstract
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.
Highlights
Serum amyloid A (SAA) is recognized as a major acute-phase protein released into the blood circulation in response to infection or injury (Jensen and Whitehead, 1998; Uhlar and Whitehead, 1999; Urieli-Shoval et al, 2000)
We found that higher concentrations (10 μM or 20 μM) of other formyl peptide receptor-like 1 (FPRL1) agonists, did not inhibit SAAinduced IL-8 production
We investigated the effect of LL-37 on the SAAinduced IL-8 production and chemotactic migration in human neutrophils
Summary
Serum amyloid A (SAA) is recognized as a major acute-phase protein released into the blood circulation in response to infection or injury (Jensen and Whitehead, 1998; Uhlar and Whitehead, 1999; Urieli-Shoval et al, 2000). The concentration of SAA has been reported to be 1,000 times the normal level during acute-phase reactions (Jensen and Whitehead, 1998; Uhlar and Whitehead, 1999; Urieli-Shoval et al, 2000). Su et al (1999a) demonstrated that radiolabeled SAA binds to human phagocytes and 293 FPRL1-transfected cells, demonstrating that FPRL1 is a specific SAA receptor. He et al (2003) demonstrated that SAA stimulates IL-8 production in human neutrophils by activating FPRL1. The putative molecules that can block SAA's actions are considered very useful for the development of anti-inflammatory therapeutic agents
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