IL-8 analogue CXCL8 (3-72) K11R/G31P, modulates LPS-induced inflammation via AKT1-NF-k beta and ERK1/2-AP-1 pathways in THP-1 monocytes

IL-8 is elevated during inflammation, and it initiates cascade of down-stream reactions. Its antagonist, CXCL8 (3-72) K11R/G31P (G31P), represses inflammatory reactions via competitive binding to CXC chemokine family, preferentially G protein-couple receptors (GPCRs) CXCR1/2. This study reports the effect of G31P on the transcription profile of lipopolysaccharide (LPS) induced inflammation in THP-1 monocytes ex-vivo. LPS (1 mu g/ml) induced elevation of IL-8 was significantly reduced by G31P (20 mu g/ml and 30 mu g/ml), with relatively increased inhibition of CXCR2 than CXCR1. Transcription of IL-1 beta, IL-1 beta, and TNF-alpha were significantly inhibited, while IL-10 remained relatively unchanged. G31P treatment also had repressing effect on the inflammatory associated enzymes COX-2, MMP-2, and MMP-9. Significant restriction of c-Fos, and NF-k beta mRNA expression was observed, while that of c-Jun was marginally elevated. Conversely, SP-1 mRNA expression was seen to increase appreciably by G31P treatment. While the translation of pAKT, pERK1/2, and p65- NF-k beta were down regulated by the G31P following THP-1 cells stimulation with LPS, reactive oxygen species (ROS) expression was on the positive trajectory. Collectively, the IL-8 analogue, G31P, modulates the inflammatory profile of LPS induced inflammation in THP-1 monocytes via AKT1-NF-k beta and ERK1/2-AP-1 pathways.