Anti-inﬂammatory effects of diaporisoindole B in LPS-stimulated RAW 264.7 macrophage cells via MyD88 activated NF-κB and MAPKs pathways

doi:10.5246/jcps.2021.08.055

Abstract

Abstract:

Diaporisoindole B (DPB), an isoprenylisoindole alkaloid isolated from the mangrove endophytic fungus Diaporthe sp. SYSU-HQ3, has been proved to inhibit the production of nitric oxide (NO) in lipopolysaccharide (LPS)-challenged RAW 264.7 mouse macrophages, showing potent anti-inflammatory effects. In this study, we further investigated the anti-inflammatory effects of DPB and explored the possible mechanisms in LPS-challenged RAW 264.7 mouse macrophages. The results showed that DPB (3.125, 6.2, 12.5 and 25 μM) could significantly reduce LPS-induced levels of PGE2, and inhibit the expressions of iNOS and COX-2 in a dose-dependent manner. In addition, DPB also inhibited LPS-induced production of inflammatory cytokines, including TNF-α, IL-1β, IL-6. Moreover, we further investigated signal transduction mechanisms by which DPB exerted anti-inflammatory effects. DPB could affect LPS-mediated nuclear factor kappa B (NF-κB) signaling pathway activation via down-regulating the upstream myeloid differentiation protein 88 (MyD88) at the protein level. Additionally, DPB also strongly inhibited the phosphorylation of mitogen-activated protein kinases (MAPKs), including extracellular signal-regulated kinase (ERK) 1/2, c-Jun N-terminal kinase (JNK) and p38. Therefore, DPB might exert anti-inflammatory effects by suppressing NF-κB activation and MAPKs pathways via down-regulating MyD88 in RAW 264.7 cells.

Key words: Diaporisoindole B, Anti-in?ammation, RAW 264.7 macrophage cells, NF-κB, MAPKs, MyD88

Supporting:

Hongju Liu, Jing Li, Huiyi Xie, Lingling Wang, Zhizhen Zhang, Chong Yan. Anti-inﬂammatory effects of diaporisoindole B in LPS-stimulated RAW 264.7 macrophage cells via MyD88 activated NF-κB and MAPKs pathways[J]. Journal of Chinese Pharmaceutical Sciences, 2021, 30(8): 675-685.

Figures/Tables 7

References 33

[1]	Zhang, X.; Wang, G.; Gurley, E.C.; Zhou, H. Flavonoid apigenin inhibits lipopolysaccharide-induced inflammatory response through multiple mechanisms in macrophages. PLoS. One. 2014, 9, e107072.
[2]	Jeong, D.; Yi, Y.S.; Sung, G.H.; Yang, W.S.; Park, J.G.; Yoon, K.; Yoon, D.H.; Song, C.; Lee, Y.; Rhee, M.H.; Kim, T.W.; Kim, J.H.; Cho, J.Y. Anti-inflammatory activities and mechanisms of Artemisia asiatica ethanol extract. J. Ethnopharmacol. 2014, 152, 487–496.
[3]	Heo, S.J.; Yoon, W.J.; Kim, K.N.; Ahn, G.N.; Kang, S.M.; Kang, D.H.; Affan, A.; Oh, C.; Jung, W.K.; Jeon, Y.J. Evaluation of anti-inflammatory effect of fucoxanthin isolated from brown algae in lipopolysaccharide-stimulated RAW 264.7 macrophages. Food Chem. Toxicol. 2010, 48, 2045–2051.
[4]	Wang, Y.; Liu, S.L.; Li, Y.; Wang, Q.; Shao, J.R.; Chen, Y.; Xin, J.Q. Mycoplasma bovis-derived lipid-associated membrane proteins activate IL-1β production through the NF-κB pathway via toll-like receptor 2 and MyD88. Dev. Comp. Immunol. 2016, 55, 111–118.
[5]	Janssens, S.; Burns, K.; Tschopp, J.; Beyaert, R. Regulation of interleukin-1- and lipopolysaccharide-induced NF-κB activation by alternative splicing of MyD88. Curr. Biol. 2002, 12, 467–471.
[6]	Jung, W.K.; Ahn, Y.W.; Lee, S.H.; Choi, Y.H.; Kim, S.K.; Yea, S.S.; Choi, I.; Park, S.G.; Seo, S.K.; Lee, S.W.; Choi, I.W. Ecklonia cava ethanolic extracts inhibit lipopolysaccharide-induced cyclooxygenase-2 and inducible nitric oxide synthase expression in BV₂ microglia via the MAP kinase and NF-κB pathways. Food Chem. Toxicol. 2009, 47, 410–417.
[7]	Gao, J.W. Curcumin inhibits inflammatory cytokine transcription via the apoptosis pathway in THP-1 cells. J. Chin. Pharm. Sci. 2019, 28, 100–113.
[8]	Hong, Q.; Wang Z.H.; Yang, Y.; Gao, L.; Yan, Z. DGMI alleviates OGD/R-induced cell injury by regulating inflammatory and apoptosis signaling pathways. J. Chin. Pharm. Sci. 2020, 29, 455–469.
[9]	Kyriakis, J.M.; Avruch, J. Mammalian MAPK signal transduction pathways activated by stress and inflammation: a 10-year update. Physiol. Rev. 2012, 92, 689–737.
[10]	Kim, S.H.; Kim, J.; Sharma, R.P. Inhibition of p38 and ERK MAP kinases blocks endotoxin-induced nitric oxide production and differentially modulates cytokine expression. Pharmacol. Res. 2004, 49, 433–439.
[11]	Fan, G.W.; Zhang, Y.; Jiang, X.R.; Zhu, Y.; Wang, B.Y.; Su, L.N.; Cao, W.J.; Zhang, H.; Gao, X.M. Anti-inflammatory activity of baicalein in LPS-stimulated RAW 264.7 macrophages via estrogen receptor and NF-κB-dependent pathways. Inflammation. 2013, 36, 1584–1591.
[12]	Lee, J.W.; Kim, N.H.; Kim, J.Y.; Park, J.H.; Shin, S.Y.; Kwon, Y.S.; Lee, H.J.; Kim, S.S.; Chun, W. Aromadendrin inhibits lipopolysaccharide-induced nuclear translocation of NF-κB and phosphorylation of JNK in RAW 264.7 macrophage cells. Biomol. Ther. 2013, 21, 216–221.
[13]	Carroll, A.R.; Copp, B.R.; Davis, R.A.; Keyzers, R.A.; Prinsep, M.R. Marine natural products. Nat. Prod. Rep. 2020, 37, 175–223.
[14]	Carroll, A.R.; Copp, B.R.; Davis, R.A.; Keyzers, R.A.; Prinsep, M.R. Marine natural products. Nat. Prod. Rep. 2020, 37, 175–223.
[15]	Xu, J. Bioactive natural products derived from mangrove-associated microbes. RSC Adv. 2015, 5, 841–892.
[16]	Cui, H.; Liu, Y.N.; Li, J.; Huang, X.S.; Yan, T.; Cao, W.H.; Liu, H.J.; Long, Y.H.; She, Z.G. Diaporindenes A-D: four unusual 2, 3-dihydro-1H-indene analogues with anti-inflammatory activities from the mangrove endophytic fungus diaporthe sp. SYSU-HQ3. J. Org. Chem. 2018, 83, 11804–11813.
[17]	Lee, S.R.; Lee, S.; Moon, E.; Park, H.J.; Park, H.B.; Kim, K.H. Bioactivity-guided isolation of anti-inflammatory triterpenoids from the sclerotia of Poria Cocos using LPS-stimulated RAW 264.7 cells. Bioorg. Chem. 2017, 70, 94–99.
[18]	Yang, Y.I.; Shin, H.C.; Kim, S.H.; Park, W.Y.; Lee, K.T.; Choi, J.H. 6, 6'-Bieckol, isolated from marine alga Ecklonia cava, suppressed LPS-induced nitric oxide and PGE2 production and inflammatory cytokine expression in macrophages: The inhibition of NFκB. Int. Immunopharmacol. 2012, 12, 510–517.
[19]	Baek, K.S.; Hong, Y.D.; Kim, Y.; Sung, N.Y.; Yang, S.; Lee, K.M.; Park, J.Y.; Park, J.S.; Rho, H.S.; Shin, S.S.; Cho, J.Y. Anti-inflammatory activity of AP-SF, a ginsenoside-enriched fraction, from Korean ginseng. J. Ginseng Res. 2015, 39, 155–161.
[20]	Yayeh, T.; Jung, K.H.; Jeong, H.Y.; Park, J.H.; Song, Y.B.; Kwak, Y.S.; Kang, H.S.; Cho, J.Y.; Oh, J.W.; Kim, S.K.; Rhee, M.H. Korean red ginseng saponin fraction downregulates proinflammatory mediators in LPS stimulated RAW 264.7 cells and protects mice against endotoxic shock. J. Ginseng Res. 2012, 36, 263–269.
[21]	Zhou, H.Y.; Shin, E.M.; Guo, L.Y.; Youn, U.J.; Bae, K.; Kang, S.S.; Zou, L.B.; Kim, Y.S. Anti-inflammatory activity of 4-methoxyhonokiol is a function of the inhibition of iNOS and COX-2 expression in RAW 264.7 macrophages via NF-κB, JNK and p38 MAPK inactivation. Eur. J. Pharmacol. 2008, 586, 340–349.
[22]	Chung, E.Y.; Kim, B.H.; Hong, J.T.; Lee, C.K.; Ahn, B.; Nam, S.Y.; Han, S.B.; Kim, Y. Resveratrol down-regulates interferon-γ-inducible inflammatory genes in macrophages: molecular mechanism via decreased STAT-1 activation. J. Nutr. Biochem. 2011, 22, 902–909.
[23]	Shin, J.S.; Park, Y.M.; Choi, J.H.; Park, H.J.; Shin, M.C.; Lee, Y.S.; Lee, K.T. Sulfuretin isolated from heartwood of Rhus verniciflua inhibits LPS-induced inducible nitric oxide synthase, cyclooxygenase-2, and pro-inflammatory cytokines expression via the down-regulation of NF-κB in RAW 264.7 murine macrophage cells. Int. Immunopharmacol. 2010, 10, 943–950.
[24]	Kim, K.N.; Ko, Y.J.; Kang, M.C.; Yang, H.M.; Roh, S.W.; Oda, T.; Jeon, Y.J.; Jung, W.K.; Heo, S.J.; Yoon, W.J.; Kim, D. Anti-inflammatory effects of trans-1, 3-diphenyl-2, 3-epoxypropane-1-one mediated by suppression of inflammatory mediators in LPS-stimulated RAW 264.7 macrophages. Food Chem. Toxicol. 2013, 53, 371–375.
[25]	Niu, X.F.; Mu, Q.L.; Li, W.F.; Yao, H.; Li, H.N.; Huang, H.M. Esculentic acid, a novel and selective COX-2 inhibitor with anti-inflammatory effect in vivo and in vitro. Eur. J. Pharmacol. 2014, 740, 532–538.
[26]	Yoshimura, A. Signal transduction of inflammatory cytokines and tumor development. Cancer Sci. 2006, 97, 439–447.
[27]	Li, Q.T.; Verma, I.M. NF-kappaB regulation in the immune system. Nat. Rev. Immunol. 2002, 2, 725–734.
[28]	Takada, Y.; Singh, S.; Aggarwal, B.B. Identification of a p65 peptide that selectively inhibits NF-kappa B activation induced by various inflammatory stimuli and its role in down-regulation of NF-kappaB-mediated gene expression and up-regulation of apoptosis. J. Biol. Chem. 2004, 279, 15096–15104.
[29]	Gilmore, T.D. Introduction to NF- κ B: players, pathways, perspectives. Oncogene. 2006, 25, 6680–6684.
[30]	Li, X.N.; Su, J.; Zhao, L.; Xiang, J.B.; Wang, W.H.; Liu, F.; Li, H.Y.; Zhong, J.T.; Bai, X.; Sun, L.K. The p38 MAPK inhibitor JLU1124 inhibits the inflammatory response induced by lipopolysaccharide through the MAPK-NF-κB pathway in RAW 264.7 macrophages. Int. Immunopharmacol. 2013, 17, 785–792.
[31]	Bao, M.H.; Zhang, Y.W.; Zhou, H.H. Paeonol suppresses oxidized low-density lipoprotein induced endothelial cell apoptosis via activation of LOX-1/p38MAPK/NF-κB pathway. J. Ethnopharmacol. 2013, 146, 543–551.
[32]	Kim, S.H.; Kim, J.; Sharma, R.P. Inhibition of p38 and ERK MAP kinases blocks endotoxin-induced nitric oxide production and differentially modulates cytokine expression. Pharmacol. Res. 2004, 49, 433–439.
[33]	McGuire, V.A.; Gray, A.; Monk, C.E.; Santos, S.G.; Lee, K.; Aubareda, A.; Crowe, J.; Ronkina, N.; Schwermann, J.; Batty, I.H.; Leslie, N.R.; Dean, J.L.E.; O'Keefe, S.J.; Boothby, M.; Gaestel, M.; Arthur, J.S.C. Cross talk between the Akt and p38α pathways in macrophages downstream of toll-like receptor signaling. Mol. Cell Biol. 2013, 33, 4152–4165.