Marine Microorganism-Derived Macrolactins Inhibit Inflammatory Mediator Effects in LPS-Induced Macrophage and Microglial Cells by Regulating BACH1 and HO-1/Nrf2 Signals through Inhibition of TLR4 Activation.

Eun-Nam Kim,Gil-Saeng Jeong,Hyukjae Choi,Ming Gao

doi:10.3390/molecules25030656

Eun-Nam Kim, Gil-Saeng Jeong + Show 2 more

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https://doi.org/10.3390/molecules25030656

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Abstract

Recently, many natural products with unique structure and promising pharmacological potential have been reported from marine-derived microorganisms. The macrolactin A (MA), 15-epi-dihydromacrolactin F (DMF) and macrolactin F (MF) were obtained from the culture broth extract of a marine sediment derived microorganism Bacillus sp. HC001. In this study, MA, DMF and MF inhibited the production and expression of proinflammatory mediators of inducible nitric oxide synthase (iNOS) and cyclooxygenase–2 (COX-2) in LPS-stimulated RAW264.7 and BV2 cells. Also, MA, DMF and MF exert anti-inflammatory effects through the expression of heme oxygenase (HO) -1, a stress-inducing enzyme that converts heme to carbon monoxide (CO), iron and biliberdine. Toll-like receptor 4 (TLR4) expressed by lipopolysaccharide (LPS) was inhibited by increased expression of HO-1 transcription factor Nrf2 and down regulation of BTB Domain And CNC Homolog 1 (BACH1), inhibited phosphorylation of Mitogen-activated protein kinase kinase kinase 7 (MAP3K7, TAK1) and nuclear factor kappaB (NF-κB). These results show that MA, DMF and MF effectively inhibited TLR4 by regulating BACH1 and HO-1/Nrf2 signals in LPS-stimulated RAW264.7 and BV2 cells, which suggests the possibility of use as an anti-inflammatory agent.

Highlights

Toll-like receptor 4 (TLR4) activated by LPS activates mitogen-activated protein kinase (MAPK) and nuclear factor B (NF-κB) to induce the production of inflammatory mediators and expresses inflammatory factors including matrix metallopeptidases (MMP), cyclooxygenase-2 (COX–2) and inducible nitric oxide synthase
As a result it was found that inducible nitric oxide synthase (iNOS) and COX-2, which were increased in RAW264.7 and BV2 by LPS, were inhibited in a concentration-dependent manner by macrolactin A (MA) (Figure 3a), dihydromacrolactin F (DMF) (Figure 3b) and macrolactin F (MF) (Figure 3c). These results suggest that inhibition of iNOS and COX-2 expression by MA, DMF and MF inhibited nitric oxide (NO) and prostaglandin E2 (PGE2) production
The main pattern recognition receptor TLR4 in LPS-induced inflammation is involved in the expression of pro-inflammatory genes and secretion of pro-inflammatory molecules by NF-κB and MAPK activation, which plays an important role in the release of pro-inflammatory mediators such as TNF-α, IL-1β, Interleukin 6 (IL-6) and PGE2 [39,40]

Summary

Introduction

In the innate immune response, macrophages and microglia serve as the bodys first line of defense against pathogen invasion and play an important role in promoting cellular protection and repair [3,4]. The activation of macrophages and microglia plays an important role in host defense responses to infectious agents by releasing inflammatory cytokine tumor necrosis factor-alpha (TNF-α), interleukin and pro-inflammatory mediators nitric oxide (NO) [5,6]. Molecules 2020, 25, 656 controls early inflammatory responses and plays an important role in inducing the innate immune system [7]. TLR4 activated by LPS activates mitogen-activated protein kinase (MAPK) and nuclear factor B (NF-κB) to induce the production of inflammatory mediators and expresses inflammatory factors including matrix metallopeptidases (MMP), cyclooxygenase-2 (COX–2) and inducible nitric oxide synthase (iNOS). Induction of the TLR4 pathway is required for LPS-stimulated expression [8]

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