5-Methoxyl Aesculetin Abrogates Lipopolysaccharide-Induced Inflammation by Suppressing MAPK and AP-1 Pathways in RAW 264.7 Cells

Abstract

For the first time, a pale amorphous coumarin derivative, 5-methoxyl aesculetin (MOA), was isolated from the dried bark of Fraxinus rhynchophylla Hance (Oleaceae). MOA modulates cytokine expression in lipopolysaccharide (LPS)-treated RAW 264.7 macrophages, but the precise mechanisms are still not fully understood. We determined the effects of MOA on the production of inflammatory mediators and pro-inflammatory cytokines in the LPS-induced inflammatory responses of RAW 264.7 macrophages. MOA significantly inhibited the LPS-induced production of nitric oxide (NO), prostaglandin E2 (PGE2), tumor necrosis factor-α (TNF-α), interleukin-6, and interleukin-1β. It also effectively attenuated inducible nitric oxide (NO) synthase, cyclooxygenase-2, and TNF-α mRNA expression and significantly decreased the levels of intracellular reactive oxygen species. It inhibited phosphorylation of the extracellular signal-regulated kinase (ERK1/2), thus blocking nuclear translocation of activation protein (AP)-1. In a molecular docking study, MOA was shown to target the binding site of ERK via the formation of three hydrogen bonds with two residues of the kinase, which is sufficient for the inhibition of ERK. These results suggest that the anti-inflammatory effects of MOA in RAW 264.7 macrophages derive from its ability to block both the activation of mitogen-activated protein kinases (MAPKs) and one of their downstream transcription factors, activator protein-1 (AP-1). Our observations support the need for further research into MOA as a promising therapeutic agent in inflammatory diseases.

CD200 Modulates S. aureus-Induced Innate Immune Responses Through Suppressing p38 Signaling

“…Mitogen-activated protein kinases (MAPKs), including the p38 MAPK, the extracellular-regulated kinase 1/2 (ERK1/2), and the c-Jun N-terminal kinase (JNK), play a key role in immune and inflammatory responses [19,20,21,22,23]. In the present study, we found that S. aureus stimulation activated three major MAPKs in mouse PEMs, among which, the activation of p38 MAPK was significantly enhanced upon CD200 siRNA treatment (Figure 6A–D).…”

Recombinant CC16 protein inhibits the production of pro-inflammatory cytokines via NF-κB and p38 MAPK pathways in LPS-activated RAW264.7 macrophages

“…Because NF-κB and AP-1 have been implicated in the transcriptional activation of various inflammatory cytokines [ 17 , 18 ], the effects of rCC16 on these signaling pathways were investigated by luciferase reporter assay and EMSA. As shown in Fig.…”

Anti-Inflammatory Effects of Chloranthalactone B in LPS-Stimulated RAW264.7 Cells

“…LPS, a well-known macrophage activator, is recognized by pattern-recognition receptors (PRRs), including toll-like receptor 4 (TLR4), which subsequently activates downstream signal transduction pathways such as mitogen-activated protein kinases (MAPKs), which leads to the activation of transcriptional factors such as nuclear factor (NF)-κB, interferon regulatory factor (IRF)-3, and activator protein (AP)-1 [7,8,9]. The pathogenesis of inflammation is a complicated process that leads to the production of various molecules and pro-inflammatory products such as nitrite oxide (NO), prostaglandin E 2 (PGE 2 ), tumor necrosis factor α (TNF-α), interleukin-1β (IL-1β), IL-6, and monocyte chemotactic protein-1 (MCP-1) [10,11]. Therefore, these pro-inflammatory mediators are considered important targets for the development of anti-inflammatory agents.…”