Effects of isoflavone derivatives on the production of inflammatory cytokines by synovial cells

Mijiti,Nuerbiyemu; Someya,Akimasa; Nagaoka,Isao

doi:10.3892/etm.2021.10735

Effects of isoflavone derivatives on the production of inflammatory cytokines by synovial cells

Authors:
- Nuerbiyemu Mijiti
- Akimasa Someya
- Isao Nagaoka
View Affiliations

Affiliations: Department of Host Defense and Biochemical Research, Juntendo University, Graduate School of Medicine, Tokyo 113‑8421, Japan
Published online on: September 16, 2021 https://doi.org/10.3892/etm.2021.10735
Article Number: 1300

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

The present study investigated the effects of isoflavone derivatives (daidzein, genistein and glycitein) on the production of inflammatory cytokines (IL‑6 and IL‑8) by IL‑1β‑stimulated synovial cells. Synovial MH7A cells were stimulated with IL‑1β in the absence or presence of isoflavone derivatives, and IL‑6 and IL‑8 production was measured by ELISA. The results of the present study indicated that daidzein significantly inhibited the production of IL‑6, but not IL‑8. Conversely, neither genistein nor glycitein exerted any inhibitory effects on the production of IL‑6 or IL‑8 by IL‑1β‑stimulated synovial cells. To elucidate the molecular mechanisms underlying the daidzein‑mediated inhibition of IL‑6 production, the present study examined the effects of daidzein on the phosphorylation (activation) of NF‑κB p65, ERK1/2 and p38 MAPK. Daidzein significantly inhibited the phosphorylation of NF‑κB p65 and ERK1/2, but not p38 MAPK in IL‑1β‑stimulated MH7A cells. The present study revealed that among the isoflavone derivatives examined (daidzein, genistein and glycitein), daidzein inhibited the production of IL‑6, but not IL‑8, by IL‑1β‑stimulated synovial MH7A cells via the suppression of NF‑κB p65 and ERK1/2 activation. Collectively, these results suggested that daidzein may have potential as a therapeutic agent for the treatment of arthritic disorders through its anti‑inflammatory effects via the inhibition of IL‑6 production.

View Figures

View References

1	Huber LC, Distler O, Tarner I, Gay RE, Gay S and Pap T: Synovial fibroblasts: Key players in rheumatoid arthritis. Rheumatol (Oxford). 45:669–675. 2006.PubMed/NCBI View Article : Google Scholar
2	Mathiessen A and Conaghan PG: Synovitis in osteoarthritis: Current understanding with therapeutic implications. Arthritis Res Ther. 19(18)2017.PubMed/NCBI View Article : Google Scholar
3	Storch H, Zimmermann B, Resch B, Tykocinski LO, Moradi B, Horn P, Kaya Z, Blank N, Rehart S, Thomsen M, et al: Activated human B cells induce inflammatory fibroblasts with cartilage-destructive properties and become functionally suppressed in return. Ann Rheum Dis. 75:924–32. 2016.PubMed/NCBI View Article : Google Scholar
4	Wojdasiewicz P, Poniatowski ŁA and Szukiewicz D: The role of inflammatory and anti-inflammatory cytokines in the pathogenesis of osteoarthritis. Mediators Inflamm. 2014(561459)2014.PubMed/NCBI View Article : Google Scholar
5	Pelletier JP, Martel-Pelletier J and Abramson SB: Osteoarthritis, an inflammatory disease: Potential implication for the selection of new therapeutic targets. Arthritis Rheum. 44:1237–1247. 2001.PubMed/NCBI View Article : Google Scholar
6	Malemud CJ: Biologic basis of osteoarthritis: State of the evidence. Curr Opin Rheumatol. 27:289–294. 2015.PubMed/NCBI View Article : Google Scholar
7	Barnes S, Prasain J, D'Alessandro T, Arabshahi A, Botting N, Lila MA, Jackson G, Janle E and Weaver CM: The metabolism and analysis of isoflavones and other dietary polyphenols in foods and biological systems. Food Funct. 2:235–244. 2011.PubMed/NCBI View Article : Google Scholar
8	Barnes S: The biochemistry, chemistry and physiology of the isoflavones in soybeans and their food products. Lymphat Res Biol. 8:89–98. 2010.PubMed/NCBI View Article : Google Scholar
9	Beck V, Rohr U and Jungbauer A: Phytoestrogens derived from red clover: An alternative to estrogen replacement therapy? J Steroid Biochem Mol Biol. 94:499–518. 2005.PubMed/NCBI View Article : Google Scholar
10	Munro IC, Harwood M, Hlywka JJ, Stephen AM, Doull J, Flamm WG and Adlercreutz H: Soy isoflavones: A safety review. Nutr Rev. 61:1–33. 2003.PubMed/NCBI View Article : Google Scholar
11	Vitale DC, Piazza C, Melilli B, Drago F and Salomone S: Isoflavones: Estrogenic activity, biological effect and bioavailability. Eur J Drug Metab Pharmacokinet. 38:15–25. 2013.PubMed/NCBI View Article : Google Scholar
12	Morito K, Hirose T, Kinjo J, Hirakawa T, Okawa M, Nohara T, Ogawa S, Inoue S, Muramatsu M and Masamune Y: Interaction of phytoestrogens with estrogen receptors alpha and beta. Biol Pharm Bull. 24:351–356. 2001.PubMed/NCBI View Article : Google Scholar
13	Rodriguez-Roque MJ, Rojas-Grau MA, Elez-Martinez P and Martin-Belloso O: Soymilk phenolic compounds, isoflavones and antioxidant activity as affected by in vitro gastrointestinal digestion. Food Chem. 136:206–212. 2013.PubMed/NCBI View Article : Google Scholar
14	Chacko BK, Chandler RT, D'Alessandro TL, Mundhekar A, Khoo NK, Botting N, Barnes S and Patel PP: Anti-inflammatory effects of isoflavones are dependent on flow and human endothelial cell PPARgamma. J Nutr. 137:351–356. 2007.PubMed/NCBI View Article : Google Scholar
15	Hong H, Landauer MR, Foriska MA and Ledney GD: Antibacterial activity of the soy isoflavone genistein. J Basic Microbiol. 46:329–335. 2006.PubMed/NCBI View Article : Google Scholar
16	Kang JL, Lee HW, Lee HS, Pack IS, Chong Y, Castranova V and Koh Y: Genistein prevents nuclear factor-kappa B activation and acute lung injury induced by lipopolysaccharide. Am J Respir Crit Care Med. 164:2206–2212. 2001.PubMed/NCBI View Article : Google Scholar
17	Verdrengh M, Jonsson IM, Holmdahl R and Tarkowski A: Genistein as an anti-inflammatory agent. Inflamm Res. 52:341–346. 2003.PubMed/NCBI View Article : Google Scholar
18	Hooshmand S, Soung do Y, Lucas EA, Madihally SV, Levenson CW and Arjmandi BH: Genistein reduces the production of proinflammatory molecules in human chondrocytes. J Nutr Biochem. 18:609–614. 2007.PubMed/NCBI View Article : Google Scholar
19	Li J, Li J, Yue Y, Hu Y, Cheng W, Liu R, Pan X and Zhang P: Genistein suppresses tumor necrosis factor alpha-induced inflammation via modulating reactive oxygen species/Akt/nuclear factor κB and adenosine monophosphate-activated protein kinase signal pathways in human synoviocyte MH7A cells. Drug Des Devel Ther. 8:315–323. 2014.PubMed/NCBI View Article : Google Scholar
20	Choi EY, Jin JY, Lee JY, Choi JI, Choi IS and Kim SJ: Anti-inflammatory effects and the underlying mechanisms of action of daidzein in murine macrophages stimulated with Prevotella intermedia lipopolysaccharide. J Periodontal Res. 47:204–211. 2012.PubMed/NCBI View Article : Google Scholar
21	Sheu F, Lai HH and Yen GC: Suppression effect of soy isoflavones on nitric oxide production in RAW 264.7 macrophages. J Agric Food Chem. 49:1767–1772. 2001.PubMed/NCBI View Article : Google Scholar
22	Yamagishi Y, Someya A, Imai K, Nagao J and Nagaoka I: Evaluation of the anti-inflammatory actions of various functional food materials including glucosamine on synovial cells. Mol Med Rep. 16:1353–1359. 2017.PubMed/NCBI View Article : Google Scholar
23	Yamagishi Y, Someya A and Nagaoka I: Citrulline cooperatively exerts an anti-inflammatory effect on synovial cells with glucosamine and N-acetylglucosamine. Biomed Rep. 13:37–42. 2020.PubMed/NCBI View Article : Google Scholar
24	Someya A, Ikegami T, Sakamoto K and Nagaoka I: Glucosamine downregulates the IL-1beta-induced expression of proinflammatory cytokine genes in human synovial MH7A cells by O-GlcNAc modification-dependent and -independent mechanisms. PLoS One. 11(e0165158)2016.PubMed/NCBI View Article : Google Scholar
25	Barnes PJ and Karin M: Nuclear factor-kappaB: A pivotal transcription factor in chronic inflammatory diseases. N Engl J Med. 336:1066–1071. 1997.PubMed/NCBI View Article : Google Scholar
26	Kyriakis JM and Avruch J: Mammalian MAPK signal transduction pathways activated by stress and inflammation: A 10-year update. Physiol Rev. 92:689–737. 2012.PubMed/NCBI View Article : Google Scholar
27	Tak PP and Firestein GS: NF-kappaB: A key role in inflammatory diseases. J Clin Invest. 107:7–11. 2001.PubMed/NCBI View Article : Google Scholar
28	Hamalainen M, Nieminen R, Vuorela P, Heinonen M and Moilanen E: Anti-inflammatory effects of flavonoids: genistein, kaempferol, quercetin, and daidzein inhibit STAT-1 and NF-kappaB activations, whereas flavone, isorhamnetin, naringenin, and pelargonidin inhibit only NF-kappaB activation along with their inhibitory effect on iNOS expression and NO production in activated macrophages. Mediators Inflamm. 2007(45673)2007.PubMed/NCBI View Article : Google Scholar
29	Weber A, Wasiliew P and Kracht M: Interleukin-1 (IL-1) pathway. Sci Signal. 3(cm1)2010.PubMed/NCBI View Article : Google Scholar
30	Kawai T and Akira S: TLR signaling. Semin Immunol. 19:24–32. 2007.PubMed/NCBI View Article : Google Scholar
31	Zandi E and Karin M: Bridging the gap: Composition, regulation, and physiological function of the IkappaB kinase complex. Mol Cell Biol. 19:4547–4551. 1999.PubMed/NCBI View Article : Google Scholar
32	Zandi E, Chen Y and Karin M: Direct phosphorylation of IkappaB by IKKalpha and IKKbeta: Discrimination between free and NF-kappaB-bound substrate. Science. 281:1360–1363. 1998.PubMed/NCBI View Article : Google Scholar
33	Sabio G and Davis RJ: TNF and MAP kinase signalling pathways. Semin Immunol. 26:237–245. 2014.PubMed/NCBI View Article : Google Scholar
34	Georganas C, Liu H, Perlman H, Hoffmann A, Thimmapaya B and Pope RM: Regulation of IL-6 and IL-8 expression in rheumatoid arthritis synovial fibroblasts: The dominant role for NF-kappa B but not C/EBP beta or c-Jun. J Immunol. 165:7199–7206. 2000.PubMed/NCBI View Article : Google Scholar
35	Saccani S, Pantano S and Natoli G: p38-Dependent marking of inflammatory genes for increased NF-kappa B recruitment. Nat Immunol. 3:69–75. 2002.PubMed/NCBI View Article : Google Scholar
36	Hoffmann E, Dittrich-Breiholz O, Holtmann H and Kracht M: Multiple control of interleukin-8 gene expression. J Leukoc Biol. 72:847–855. 2002.PubMed/NCBI
37	Hoffmann E, Thiefes A, Buhrow D, Dittrich-Breiholz O, Schneider H, Resch K and Kracht M: MEK1-dependent delayed expression of Fos-related antigen-1 counteracts c-Fos and p65 NF-kappaB-mediated interleukin-8 transcription in response to cytokines or growth factors. J Biol Chem. 280:9706–9718. 2005.PubMed/NCBI View Article : Google Scholar
38	Srirangan S and Choy EH: The role of interleukin 6 in the pathophysiology of rheumatoid arthritis. Ther Adv Musculoskelet Dis. 2:247–56. 2010.PubMed/NCBI View Article : Google Scholar
39	Takahashi A, de Andres MC, Hashimoto K, Itoi E and Oreffo RO: Epigenetic regulation of interleukin-8, an inflammatory chemokine, in osteoarthritis. Osteoarthritis Cartilage. 23:1946–1954. 2015.PubMed/NCBI View Article : Google Scholar