Atraric Acid Exhibits Anti-Inflammatory Effect in Lipopolysaccharide-Stimulated RAW264.7 Cells and Mouse Models.

Seul-Ki Mun,Seong-Gyeol Hong,Hyun-Wook Cho,Jae-Seoun Hur,Sung-Tae Yee,Su-Jin Kim,Ho-Yeol Jang,Kyung-Yun Kang,Dong-Jo Chang,Yun-Ho Hwang

doi:10.3390/ijms21197070

Seul-Ki Mun, Seong-Gyeol Hong + Show 8 more

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https://doi.org/10.3390/ijms21197070

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Abstract

Lichens, composite organisms resulting from the symbiotic association between the fungi and algae, produce a variety of secondary metabolites that exhibit pharmacological activities. This study aimed to investigate the anti-inflammatory activities of the secondary metabolite atraric acid produced by Heterodermia hypoleuca. The results confirmed that atraric acid could regulate induced pro-inflammatory cytokine, nitric oxide, prostaglandin E2, induced nitric oxide synthase and cyclooxygenase-2 enzyme expression in lipopolysaccharide (LPS)-stimulated RAW264.7 cells. Meanwhile, atraric acid downregulated the expression of phosphorylated IκB, extracellular signal-regulated kinases (ERK) and nuclear factor kappa B (NFκB) signaling pathway to exhibit anti-inflammatory effects in LPS-stimulated RAW264.7 cells. Based on these results, the anti-inflammatory effect of atraric acid during LPS-induced endotoxin shock in a mouse model was confirmed. In the atraric acid treated-group, cytokine production was decreased in the peritoneum and serum, and each organ damaged by LPS-stimulation was recovered. These results indicate that atraric acid has an anti-inflammatory effect, which may be the underlying molecular mechanism involved in the inactivation of the ERK/NFκB signaling pathway, demonstrating its potential therapeutic value for treating inflammatory diseases.

Highlights

Inflammation is an inherent immune mechanism that occurs as a result of pathogen invasion in the body [1,2]
At first, examining the cytotoxicity of hyterodermia hypoleuca (HH) extract in RAW264.7 cells using cell counting kit-8 (CCK-8), we observed that the growth of the cells was not affected by the HH extracts (Figure 1a)
The levels of pro-inflammatory, such as Tumor necrosis factor-alpha (TNF-α), interleukin l beta (IL-1β), interleukin 6 (IL-6) and granulocyte–macrophage colony-stimulating factor (GM-CSF) released in LPS-stimulated RAW 264.7 cells were significantly reduced by 20%, 30%, 58% and 45%, respectively, at 30 μg/mL of HH (Figure 1c–f)

Summary

Introduction

Inflammation is an inherent immune mechanism that occurs as a result of pathogen invasion in the body [1,2]. Nuclear factor-kappa B (NFκB), which regulates the transcription of inflammatory factors induced by lipopolysaccharide (LPS) stimulation, binds to IκB in the cytoplasm and activated by phosphorylation and IκB degradation. High inflammatory response results in severe tissue damage and endotoxin shock. Endotoxin shock is a severe inflammatory reaction caused by Gram-negative bacteria infection of the bloodstream. LPS, an endotoxin on the surface of Gram-negative organisms, stimulates the release of pro-inflammatory cytokines and NO, resulting in increasing vasodilation and vascular permeability. This leads to impaired cardiovascular function, pulmonary dysfunction, acute renal impairment, septic shock and, death. Many studies have demonstrated that the inhibition of NFκB and MAPK activation is an important strategy for the treatment of inflammatory diseases [8,9,10,11]

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