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Erschienen in: Rheumatology International 7/2013

01.07.2013 | Original Article

Resveratrol inhibits TNF-α-induced IL-1β, MMP-3 production in human rheumatoid arthritis fibroblast-like synoviocytes via modulation of PI3kinase/Akt pathway

verfasst von: Jing Tian, Jin-wei Chen, Jie-sheng Gao, Len Li, Xi Xie

Erschienen in: Rheumatology International | Ausgabe 7/2013

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Abstract

Resveratrol (trans-3,4′-trihydroxystilbene), a natural phytoalexin, possesses anti-inflammatory, anti-proliferative, and immunomodulatory properties and has the potential for treating inflammatory disorders. The present study was designed to investigate the effects of resveratrol on TNF-α-induced inflammatory cytokines production of IL-1β and MMP3 in Rheumatoid arthritis (RA) Fibroblast-like synoviocytes (FLS) and further to explore the role of PI3K/Akt signaling pathway by which resveratrol modulates those cytokines production. The levels of IL-1β, MMP-3 in cultural supernatants among groups were measured by enzyme-linked immunosorbent assay. Messenger RNA expression of IL-1β and MMP-3 in RA FLS was analyzed using a reverse transcription-polymerase chain reaction. Western blot analysis was used to detect proteins expression in RA FLS intervened by resveratrol. Resveratrol inhibited both mRNA and proteins expressions of IL-1β and MMP-3 on RA FLS in a dose-dependent manner. Resveratrol also decreased significantly the expression of phosphorylated Akt dose dependently. Activation of PI3K/Akt signaling pathway exists in TNF-α-induced production of IL-1β and MMP3 on RA FLS, which is hampered by PI3K inhibitor LY294002. Immunofluorescence staining showed that TNF-α alone increased the production of P-Akt, whereas LY294002 and 50 μM resveratrol suppressed the TNF-α-stimulated expression of P-Akt. Resveratrol attenuates TNF-α-induced production of IL-1β and MMP-3 via inhibition of PI3K-Akt signaling pathway in RA FLS, suggesting that resveratrol plays an anti-inflammatory role and might have beneficial effects in preventing and treating RA.
Literatur
1.
Zurück zum Zitat Noss EH, Brenner MB (2008) The role and therapeutic implications of fibroblast-like synoviocytes in inflammation and cartilage erosion in rheumatoid arthritis. Immunol Rev 223:252–270PubMedCrossRef Noss EH, Brenner MB (2008) The role and therapeutic implications of fibroblast-like synoviocytes in inflammation and cartilage erosion in rheumatoid arthritis. Immunol Rev 223:252–270PubMedCrossRef
2.
Zurück zum Zitat Feldmann M (2001) Pathogenesis of arthritis: recent research progression. Nat Immunol 2:771–773PubMedCrossRef Feldmann M (2001) Pathogenesis of arthritis: recent research progression. Nat Immunol 2:771–773PubMedCrossRef
3.
Zurück zum Zitat Zhang HG, Wang Y, Xie JF, Liang X, Liu D, Yang P et al (2001) Regulation of tumor necrosis factor alpha-mediated apoptosis of rheumatoid arthritis synovial fibroblasts by the protein kinase Akt. Arthr Rheum 44:1555–1567CrossRef Zhang HG, Wang Y, Xie JF, Liang X, Liu D, Yang P et al (2001) Regulation of tumor necrosis factor alpha-mediated apoptosis of rheumatoid arthritis synovial fibroblasts by the protein kinase Akt. Arthr Rheum 44:1555–1567CrossRef
4.
Zurück zum Zitat Reedquist KA, Ludikhuize J, Tak PP (2006) Phosphoinositide 3-kinase signalling and FoxO transcription factors in rheumatoid arthritis. Biochem Soc Trans 34:727–730PubMedCrossRef Reedquist KA, Ludikhuize J, Tak PP (2006) Phosphoinositide 3-kinase signalling and FoxO transcription factors in rheumatoid arthritis. Biochem Soc Trans 34:727–730PubMedCrossRef
5.
Zurück zum Zitat Morel J, Audo R, Hahne M et al (2005) Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) induces rheumatoid arthritis synovial fibroblast proliferation through mitogen-activated protein kinases and phosphatidylinositol 3-kinase/Akt. J Biol Chem 280(16):15709–15718PubMedCrossRef Morel J, Audo R, Hahne M et al (2005) Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) induces rheumatoid arthritis synovial fibroblast proliferation through mitogen-activated protein kinases and phosphatidylinositol 3-kinase/Akt. J Biol Chem 280(16):15709–15718PubMedCrossRef
6.
Zurück zum Zitat Kim G, Jun JB, Elkon KB (2002) Necessary role of phosphatidylinositol 3-kinase in transforming growth factor beta-mediated activation of Akt in normal and rheumatoid arthritis synovial fibro blasts. Arthr Rheum 46(6):1504–1511CrossRef Kim G, Jun JB, Elkon KB (2002) Necessary role of phosphatidylinositol 3-kinase in transforming growth factor beta-mediated activation of Akt in normal and rheumatoid arthritis synovial fibro blasts. Arthr Rheum 46(6):1504–1511CrossRef
7.
Zurück zum Zitat Pap T, Franz JK, Hummel KM et al (2000) Activation of synovial fibroblasts in rheumatoid arthritis: lack of Expression of the tumour suppressor PTEN at sites of invasive growth and destruction. Arthr Res 2(1):59–64CrossRef Pap T, Franz JK, Hummel KM et al (2000) Activation of synovial fibroblasts in rheumatoid arthritis: lack of Expression of the tumour suppressor PTEN at sites of invasive growth and destruction. Arthr Res 2(1):59–64CrossRef
8.
Zurück zum Zitat Xu H, He X, Yang X et al (2007) Anti-malarial agent artesunate inhibits TNF-α induced production of proinflammatory cytokines via inhibition of NF-κB and PI3kinase/Akt signal pathway in human rheumatoid arthritis fibroblast-like synoviocytes. Rheumatology 46:920–926PubMedCrossRef Xu H, He X, Yang X et al (2007) Anti-malarial agent artesunate inhibits TNF-α induced production of proinflammatory cytokines via inhibition of NF-κB and PI3kinase/Akt signal pathway in human rheumatoid arthritis fibroblast-like synoviocytes. Rheumatology 46:920–926PubMedCrossRef
9.
Zurück zum Zitat Dhaouadi T, Sfar I, Abelmoula L et al (2007) Role of immune system, apoptosis and angiogenesis in pathogenesis of rheumatoid arthritis and joint destruction, a systematic review. Tunis Med 85:991–998PubMed Dhaouadi T, Sfar I, Abelmoula L et al (2007) Role of immune system, apoptosis and angiogenesis in pathogenesis of rheumatoid arthritis and joint destruction, a systematic review. Tunis Med 85:991–998PubMed
10.
Zurück zum Zitat Harris SJ, Foster JG (2009) Ward SG. PI3K isoforms as drug targets in inflammatory diseases: lessons from pharmacological and genetic strategies. Curr Opin Investig Drugs 10:1151–1162PubMed Harris SJ, Foster JG (2009) Ward SG. PI3K isoforms as drug targets in inflammatory diseases: lessons from pharmacological and genetic strategies. Curr Opin Investig Drugs 10:1151–1162PubMed
11.
Zurück zum Zitat Marone R, Cmiljanovic V, Giese B et al (2008) Targeting phosphoinositide 3-kinase: moving towards therapy. Biochim Biophys Acta 1784(1):159–185PubMedCrossRef Marone R, Cmiljanovic V, Giese B et al (2008) Targeting phosphoinositide 3-kinase: moving towards therapy. Biochim Biophys Acta 1784(1):159–185PubMedCrossRef
12.
Zurück zum Zitat Ameriks MK, Venable JD (2009) Small molecule inhibitors of phosphoinositide 3-kinase (PI3K) delta and gamma. Curr Top Med Chem 9(8):738–753PubMedCrossRef Ameriks MK, Venable JD (2009) Small molecule inhibitors of phosphoinositide 3-kinase (PI3K) delta and gamma. Curr Top Med Chem 9(8):738–753PubMedCrossRef
13.
Zurück zum Zitat Harikumar KB, Aggarwal BB (2008) Resveratrol: a multitargeted agent for age-associated chronic diseases. Cell Cycle 15:1020–1035CrossRef Harikumar KB, Aggarwal BB (2008) Resveratrol: a multitargeted agent for age-associated chronic diseases. Cell Cycle 15:1020–1035CrossRef
14.
Zurück zum Zitat Fröjdö S, Cozzone D, Vidal H et al (2007) Resveratrol is a class IA phosphoinositide 3-kinase inhibitor. Biochem J 406(3):511–518PubMedCrossRef Fröjdö S, Cozzone D, Vidal H et al (2007) Resveratrol is a class IA phosphoinositide 3-kinase inhibitor. Biochem J 406(3):511–518PubMedCrossRef
15.
Zurück zum Zitat Byun HS, Song JK, Kim YR et al (2008) Caspase-8 has an essential role in resveratrol-induced apoptosis of rheumatoid fibroblast-like synoviocytes. Rheumatology 47:301–308PubMedCrossRef Byun HS, Song JK, Kim YR et al (2008) Caspase-8 has an essential role in resveratrol-induced apoptosis of rheumatoid fibroblast-like synoviocytes. Rheumatology 47:301–308PubMedCrossRef
16.
Zurück zum Zitat Nakayama H, Yaguchi T, Yoshiya S et al (2012) Resveratrol induces apoptosis MH7A human rheumatoid arthritis synovial cells in a sirtuin 1-dependent manner. Rheumatol Int 32:151–157PubMedCrossRef Nakayama H, Yaguchi T, Yoshiya S et al (2012) Resveratrol induces apoptosis MH7A human rheumatoid arthritis synovial cells in a sirtuin 1-dependent manner. Rheumatol Int 32:151–157PubMedCrossRef
17.
Zurück zum Zitat Tang LL, Gao JS, Chen XR et al (2006) Inhibitory effect of resveratrol on the proliferation of synoviocytes in rheumatoid arthritis and its mechanism in vitro. Zhong Nan Da Xue Xue Bao Yi Xue Ban 31:528–533PubMed Tang LL, Gao JS, Chen XR et al (2006) Inhibitory effect of resveratrol on the proliferation of synoviocytes in rheumatoid arthritis and its mechanism in vitro. Zhong Nan Da Xue Xue Bao Yi Xue Ban 31:528–533PubMed
18.
Zurück zum Zitat Tian J, Gao J, Chen J, Li F et al (2010) Effects of resveratrol on proliferation and apoptosis of TNF-alpha induced rheumatoidarthritis fibroblast-like synoviocytes. Zhongguo Zhong Yao Za Zhi 35:1878–1882PubMed Tian J, Gao J, Chen J, Li F et al (2010) Effects of resveratrol on proliferation and apoptosis of TNF-alpha induced rheumatoidarthritis fibroblast-like synoviocytes. Zhongguo Zhong Yao Za Zhi 35:1878–1882PubMed
19.
Zurück zum Zitat Arnett FC, Edworthy SM, Bloch DA et al (1988) The American Rheumatism Association 1987 revised criteria for the classification of rheumatoid arthritis. Arthr Rheum 31:315–324CrossRef Arnett FC, Edworthy SM, Bloch DA et al (1988) The American Rheumatism Association 1987 revised criteria for the classification of rheumatoid arthritis. Arthr Rheum 31:315–324CrossRef
20.
Zurück zum Zitat McInnes IB, O’Dell JR (2010) State-of-the-art: rheumatoid arthritis. Ann Rheum Dis 69:1898–1906PubMedCrossRef McInnes IB, O’Dell JR (2010) State-of-the-art: rheumatoid arthritis. Ann Rheum Dis 69:1898–1906PubMedCrossRef
21.
Zurück zum Zitat Bongartz T, Sutton AJ, Sweeting MJ et al (2006) Anti-TNF antibody therapy in rheumatoid arthritis and the risk of serious infections and malignancies: systematic review and meta-analysis of rare harmful effects in randomized controlled trials. JAMA 295:2275–2285PubMedCrossRef Bongartz T, Sutton AJ, Sweeting MJ et al (2006) Anti-TNF antibody therapy in rheumatoid arthritis and the risk of serious infections and malignancies: systematic review and meta-analysis of rare harmful effects in randomized controlled trials. JAMA 295:2275–2285PubMedCrossRef
22.
Zurück zum Zitat Khanna D, Sethi G, Ahn KS et al (2007) Natural products as a gold mine for arthritis treatment. Curr Opin Pharmacol 7:344–351PubMedCrossRef Khanna D, Sethi G, Ahn KS et al (2007) Natural products as a gold mine for arthritis treatment. Curr Opin Pharmacol 7:344–351PubMedCrossRef
23.
Zurück zum Zitat Elmali N, Baysal O, Harma A et al (2007) Effects of resveratrol in inflammatory arthritis. Inflammation 30:1–6PubMedCrossRef Elmali N, Baysal O, Harma A et al (2007) Effects of resveratrol in inflammatory arthritis. Inflammation 30:1–6PubMedCrossRef
24.
Zurück zum Zitat Xuzhu G, Komai-Koma M, Leung BP et al (2012) Resveratrol modulates murine collagen-induced arthritis by inhibiting Th17 and B-cell function. Ann Rheum Dis 71:129–135PubMedCrossRef Xuzhu G, Komai-Koma M, Leung BP et al (2012) Resveratrol modulates murine collagen-induced arthritis by inhibiting Th17 and B-cell function. Ann Rheum Dis 71:129–135PubMedCrossRef
25.
Zurück zum Zitat Roy S, Sannigrahi S, Majumdar S et al. (2011) Resveratrol regulates antioxidant status, inhibits cytokine expression and restricts apoptosis in carbon tetrachloride induced rat hepatic injury. Oxid Med Cell Longev 703676 Roy S, Sannigrahi S, Majumdar S et al. (2011) Resveratrol regulates antioxidant status, inhibits cytokine expression and restricts apoptosis in carbon tetrachloride induced rat hepatic injury. Oxid Med Cell Longev 703676
26.
Zurück zum Zitat Culpitt SV, Rogers DF, Fenwick PS et al (2003) Inhibition by red wine extract, resveratrol, of cytokine release by alveolar macrophages in COPD. Thorax 58:942–946PubMedCrossRef Culpitt SV, Rogers DF, Fenwick PS et al (2003) Inhibition by red wine extract, resveratrol, of cytokine release by alveolar macrophages in COPD. Thorax 58:942–946PubMedCrossRef
27.
Zurück zum Zitat Kang OH, Jang HJ, Chae HS et al (2009) Anti-inflammatory mechanisms of resveratrol in activated HMC-1 cells: pivotal roles of NF-kappaB and MAPK. Pharmacol Res 59:330–337PubMedCrossRef Kang OH, Jang HJ, Chae HS et al (2009) Anti-inflammatory mechanisms of resveratrol in activated HMC-1 cells: pivotal roles of NF-kappaB and MAPK. Pharmacol Res 59:330–337PubMedCrossRef
28.
Zurück zum Zitat Poolman TM, Ng LL, Farmer PB et al (2005) Inhibition of the respiratory burst by resveratrol in human monocytes: correlation with inhibition of PI3K signaling. Free Radic Biol Med 39:118–132PubMedCrossRef Poolman TM, Ng LL, Farmer PB et al (2005) Inhibition of the respiratory burst by resveratrol in human monocytes: correlation with inhibition of PI3K signaling. Free Radic Biol Med 39:118–132PubMedCrossRef
29.
Zurück zum Zitat Jiang H, Shang X, Wu H et al (2009) Resveratrol downregulates PI3K/Akt/mTOR signaling pathways in human U251 glioma cells. J Exp Ther Oncol 8:25–33PubMed Jiang H, Shang X, Wu H et al (2009) Resveratrol downregulates PI3K/Akt/mTOR signaling pathways in human U251 glioma cells. J Exp Ther Oncol 8:25–33PubMed
30.
Zurück zum Zitat Roy P, Kalra N, Prasad S et al (2009) Chemopreventive potential of resveratrol in mouse skin tumors through regulation of mitochondrial and PI3K/AKT signaling pathways. Pharm Res 26:211–217PubMedCrossRef Roy P, Kalra N, Prasad S et al (2009) Chemopreventive potential of resveratrol in mouse skin tumors through regulation of mitochondrial and PI3K/AKT signaling pathways. Pharm Res 26:211–217PubMedCrossRef
31.
Zurück zum Zitat Benitez DA, Pozo-Guisado E, Clementi M et al (2007) Non-genomic action of resveratrol on androgen and oestrogen receptors in prostate cancer: modulation of the phosphoinositide 3-kinase pathway. Br J Cancer 96:1595–1604PubMedCrossRef Benitez DA, Pozo-Guisado E, Clementi M et al (2007) Non-genomic action of resveratrol on androgen and oestrogen receptors in prostate cancer: modulation of the phosphoinositide 3-kinase pathway. Br J Cancer 96:1595–1604PubMedCrossRef
32.
Zurück zum Zitat Camps M, Ruckle T, Ji H et al (2005) Blockade of PI3Kγ suppresses joint inflammation and damage in mouse models of rheumatoid arthritis. Nat Med 11:936–943PubMed Camps M, Ruckle T, Ji H et al (2005) Blockade of PI3Kγ suppresses joint inflammation and damage in mouse models of rheumatoid arthritis. Nat Med 11:936–943PubMed
33.
Zurück zum Zitat Randis TM, Puri KD, Zhou H et al (2008) Role of PI3Kδ and PI3Kγ in inflammatory arthritis and tissue localization of neutrophils. Eur J Immunol 38:1215–1224PubMedCrossRef Randis TM, Puri KD, Zhou H et al (2008) Role of PI3Kδ and PI3Kγ in inflammatory arthritis and tissue localization of neutrophils. Eur J Immunol 38:1215–1224PubMedCrossRef
Metadaten
Titel
Resveratrol inhibits TNF-α-induced IL-1β, MMP-3 production in human rheumatoid arthritis fibroblast-like synoviocytes via modulation of PI3kinase/Akt pathway
verfasst von
Jing Tian
Jin-wei Chen
Jie-sheng Gao
Len Li
Xi Xie
Publikationsdatum
01.07.2013
Verlag
Springer-Verlag
Erschienen in
Rheumatology International / Ausgabe 7/2013
Print ISSN: 0172-8172
Elektronische ISSN: 1437-160X
DOI
https://doi.org/10.1007/s00296-012-2657-0

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