4-(Hydroxymethyl)catechol Extracted From Fungi in Marine Sponges Attenuates Rheumatoid Arthritis by Inhibiting PI3K/Akt/NF-κB Signaling.

Jong Y. Lee,Young-Ae Choi,Jin K. Choi,Na-Hee Jeong,Sang-Hyun Kim,Hyukjae Choi,Pil-Hoon Park,Geum J. Kim

doi:10.3389/fphar.2018.00726

Abstract

Rheumatoid arthritis (RA) is a progressive autoimmune disease specific to synovial joints; it causes joint damage and other systemic abnormalities, thereby leading to physical disability and early mortality. Marine sponge-derived fungi, Pestalotiopsis sp., secrete immunosuppressive compounds in the culture broth. In the present study, we isolated 4-(hydroxymethyl)catechol (4-HMC) from these fungal species, and evaluated its anti-RA effects using a murine collagen-induced arthritis model and tumor necrosis factor-α-stimulated human RA synovial fibroblasts. Oral 4-HMC administration decreased the clinical arthritis score, paw thickness, histologic and radiologic changes, and serum IgG1 and IgG2a levels. It prevented the proliferation of helper T (Th) 1/Th17 CD4+ lymphocytes isolated from inguinal lymph nodes, thereby reducing inflammatory cytokine production in CIA mice. It decreased the expression of inflammatory mediators, including cytokines and matrix metalloproteinases (MMPs), both in vitro and in vivo. We observed that 4-HMC suppresses Th immune responses and MMP expression to inhibit inflammatory cytokine production in human RA synovial fibroblasts by modulating the PI3K/Akt/NF-κB pathway. These results verify the anti-RA potential of 4-HMC.

Highlights

Rheumatoid arthritis (RA) is characterized by articular inflammation, synovial joint damage, and bone destruction over time (McInnes et al, 2016)
The 4-HMC was isolated from the ethyl acetate extract of the culture broth of the marine fungi, Pestalotiopsis sp., as a pale brown powder; LR-ESI-MS revealed the [M + Na]+ ion at m/z 163.1. 1H NMR ABX spectra revealed proton signals at δH 6.76 (H-3, 1H, d, J = 2.8 Hz), 6.62 (H-6, 1H, d, J = 8.6 Hz), and 6.54 (H-5, 1H, J = 8.6, 2.8 Hz); an oxygenated methylene proton signal was observed at δH 4.59 (H-7, 2H, s). 13C NMR spectra exhibited two phenolic carbon signals, four aromatic carbon signals, and an oxygenated methylene carbon signal (Supplementary Figures S2, S3 and Supplementary Table S1)
No bone degradation was found in Dexa-treated mice (Figure 2D). [18F] FDG micro-Positron Emission Tomography (PET) is a recently developed in vivo imaging tool for screening anti-inflammatory or antiRA drugs

Summary

Introduction

Rheumatoid arthritis (RA) is characterized by articular inflammation, synovial joint damage, and bone destruction over time (McInnes et al, 2016). It can cause chronic pain and severe disability, thereby increasing mortality. Phagocytic cells of the innate immune system, including macrophages and dendritic cells, are implicated in RA progression (Cuda et al, 2016). These cells activate immune cells and promote their influx into the synovial tissue. Synovial fibroblasts in synovium produce cytokine, chemokines, and matrix metalloproteinases (MMPs) (Haleagrahara et al, 2018). MMPs drive cartilage erosion in RA (Noss et al, 2011).

Methods

Results

Conclusion