Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress 2023 EHA Congress 2023 ASCO Annual Meeting
Clinical Collections
Advances in Alzheimer’s

At a glance: The ONWARDS insulin icodec trials

A round-up of the ONWARDS phase 3 clinical trials evaluating the novel weekly insulin icodec in people with diabetes.
ADVANCED SEARCH
Log in
Top
Journal of Natural Medicines
Published in: Journal of Natural Medicines 2/2017

01-04-2017 | Original Paper

Shikonin inhibits TNF-α production through suppressing PKC-NF-κB-dependent decrease of IL-10 in rheumatoid arthritis-like cell model

Authors: Wen-Xiao Sun, Yan Liu, Wei Zhou, He-Wei Li, Jian Yang, Zhen-Bing Chen

Published in: Journal of Natural Medicines | Issue 2/2017

Login to get access

Abstract

Shikonin, a major effective component in the Chinese herbal medicine Lithospermum erythrorhizon Sieb., exhibits an anti-inflammatory property towards rheumatoid arthritis (RA), but the potential mechanism is unclear. Our aim was to investigate the mechanism of shikonin on the lipopolysaccharide (LPS)-induced fibroblast-like synoviocyte (LiFLS) inflammation model. Fibroblast-like synoviocytes (FLSs) were treated with 200 μg/ml of LPS for 24 h to establish the RA-like model, LiFLS. FLSs were pretreated with shikonin (0.1–1 μM) for 30 min in the treatment groups. Quantitative real-time polymerase chain reaction and enzyme-linked immunosorbent assays were used to detect mRNA and protein levels of interleukin (IL)-10 and tumor necrosis factor (TNF)-α. Signal proteins involved in IL-10 production were analyzed by Western blotting. Shikonin significantly reversed the inhibitory effects of LPS on IL-10 expression in FLSs by inactivating the PKC-NF-κB pathway. In addition, shikonin inhibited LPS-induced TNF-α expression in FLSs, and this effect was markedly diminished by IL-10-neutralizing antibody. The IL-10-mediated suppression of TNF-α transcription was demonstrated by no response to the protein synthesis inhibitor cyclohexamide and no mRNA decay. Shikonin inhibits LPS-induced TNF-α production in FLSs through suppressing the PKC-NF-κB-dependent decrease in IL-10, and this study also highlights the potential application of shikonin in the treatment of RA.
Appendix
Available only for authorised users
Literature
1.
Filippin LI, Vercelino R, Marroni N, Xavier RM (2008) Redox signalling and the inflammatory response in rheumatoid arthritis. Clin Exp Immunol 152:415–422CrossRefPubMedPubMedCentral
2.
Cheon H, Yu SJ, Yoo D, Chae I, Song G, Sohn J (2002) Increased expression of pro-inflammatory cytokines and metalloproteinase-1 by TGF-β1 in synovial fibroblasts from rheumatoid arthritis and normal individuals. Clin Exp Immunol 127:547–552CrossRefPubMedPubMedCentral
3.
Xu H, He Y, Yang X, Liang L, Zhan Z, Ye Y, Sun L (2007) Anti-malarial agent artesunate inhibits TNF-α-induced production of proinflammatory cytokines via inhibition of NF-κB and PI3 kinase/Akt signal pathway in human rheumatoid arthritis fibroblast-like synoviocytes. Rheumatology 46:920–926CrossRefPubMed
4.
5.
Kawashima M, Ogura N, Akutsu M, Ito K, Kondoh T (2013) The anti-inflammatory effect of cyclooxygenase inhibitors in fibroblast-like synoviocytes from the human temporomandibular joint results from the suppression of PGE2 production. J Oral Pathol Med 42:499–506CrossRefPubMedPubMedCentral
6.
Henry D, Lim LL, Rodriguez LAG, Gutthann SP, Carson JL, Griffin M, Savage R, Logan R, Moride Y, Hawkey C, Hill S, Fries JT (1996) Variability in risk of gastrointestinal complications with individual non-steroidal anti-inflammatory drugs: results of a collaborative meta-analysis. BMJ 312:1563–1566CrossRefPubMedPubMedCentral
7.
MacDonald T, Morant S, Robinson GC, Shield MJ, McGilchrist MM, Murray FE, McDevitt DG (1997) Association of upper gastrointestinal toxicity of non-steroidal anti-inflammatory drugs with continued exposure: cohort study. BMJ 315:1333–1337CrossRefPubMedPubMedCentral
8.
Staniforth V, Wang SY, Shyur LF, Yang NS (2004) Shikonins, phytocompounds from Lithospermum erythrorhizon, inhibit the transcriptional activation of human tumor necrosis factor α promoter in vivo. J Biol Chem 279:5877–5885CrossRefPubMed
9.
Chiu SC, Yang NS (2007) Inhibition of tumor necrosis factor-α through selective blockade of pre-mRNA splicing by shikonin. Mol Pharmacol 71:1640–1645CrossRefPubMed
10.
Lu L, Qin A, Huang H, Zhou P, Zhang C, Liu N, Li S, Wen G, Zhang C, Dong W, Wang X, Dou P, Liu J (2011) Shikonin extracted from medicinal Chinese herbs exerts anti-inflammatory effect via proteasome inhibition. Eur J Pharmacol 658:242–247CrossRefPubMedPubMedCentral
11.
Liang D, Sun Y, Shen Y, Li F, Song X, Zhou E, Zhao F, Liu Z, Fu Y, Guo M, Zhang N, Yang Z, Cao Y (2013) Shikonin exerts anti-inflammatory effects in a murine model of lipopolysaccharide-induced acute lung injury by inhibiting the nuclear factor-kappaB signaling pathway. Int Immunopharmacol 16:475–480CrossRefPubMed
12.
Kim YO, Hong SJ, Yim SV (2010) The efficacy of shikonin on cartilage protection in a mouse model of rheumatoid arthritis. Korean J Physiol Pharmacol 14:199–204CrossRefPubMedPubMedCentral
13.
Dai Q, Fang J, Zhang FS (2009) Dual role of shikonin in early and late stages of collagen type II arthritis. Mol Biol Rep 36:1597–1604CrossRefPubMed
14.
Asadullah K, Sterry W, Volk H (2003) Interleukin-10 therapy-review of a new approach. Pharmacol Rev 55:241–269CrossRefPubMed
15.
Katsikis PD, Chu CQ, Brennan FM, Maini RN, Feldmann M (1994) Immunoregulatory role of interleukin 10 in rheumatoid arthritis. J Exp Med 179:1517–1527CrossRefPubMed
16.
Llorente L, Richaud-Patin Y, Fior R, Alcocer-Varela J, Wijdenes J, Fourrier BM, Galanaud P, Emilie D (1994) In vivo production of interleukin-10 by non-T cells in rheumatoid arthritis, Sjögren’s syndrome, and systemic lupus erythematosus. Arthritis Rheum 37:1647–1655CrossRefPubMed
17.
Cush JJ, Splawski JB, Thomas R, Mcfarlin JE, Schulze-Koops H, Schulze-Koops H, Davis LS, Fujita K, Lipsky PE (1995) Elevated interleukin-10 levels in patients with rheumatoid arthritis. Arthritis Rheum 38:96–104CrossRefPubMed
18.
Moelants EA, Mortier A, Van Damme J, Proost P (2013) Regulation of TNF-α with a focus on rheumatoid arthritis. Immunol Cell Biol 91:393–401CrossRefPubMed
19.
Jobin C, Haskill S, Mayer L, Panja A, Sartor RB (1997) Evidence for altered regulation of I kappa B alpha degradation in human colonic epithelial cells. J Immunol 158:226–234PubMed
20.
Song SS, Huang B, Wang QT, Wu YJ, Fu JJ, Zhang YF, Chang Y, Chen ZY, Wu HX, Wang D, Zhang LL, Wei W (2013) BF02, a recombinant TNFR2 fusion protein, alleviates adjuvant arthritis by regulating T lymphocytes in rats. Acta Pharmacol Sin 34:414–423CrossRefPubMedPubMedCentral
21.
Matsuda S, Uchikawa R, Yamada M, Arizono N (1995) Cytokine mRNA expression profiles in rats infected with the intestinal nematode Nippostrongylus brasiliensis. Infect Immun 63:4653–4660PubMedPubMedCentral
22.
Padegimas L, Kowalczyk TH, Adams S, Gedeon CR, Oette SM, Dines K, Hyatt SL, Sesenoglu-Laird O, Tyr O, Moen RC, Cooper MJ (2012) Optimization of hCFTR lung expression in mice using DNA nanoparticles. Mol Ther 20:63–72CrossRefPubMed
23.
Matsuno H, Yudoh K, Katayama R, Nakazawa F, Uzuki M, Sawai T, Yonezawa T, Saeki Y, Panayi GS, Pitzalis C (2002) The role of TNF-α in the pathogenesis of inflammation and joint destruction in rheumatoid arthritis (RA): a study using a human RA/SCID mouse chimera. Rheumatology 41:329–337CrossRefPubMed
24.
Noh KT (2014) Protein kinase C delta (PKCδ)- extracellular-signal regulated kinase 1/2 (ERK1/2) signaling cascade regulates glycogen synthase kinase-3 (GSK-3) inhibition- mediated interleukin-10 (IL-10) expression in lipopolysaccharide (LPS)-induced endotoxemia (IRM5P. 704). J Immunol 192:62–65
25.
La Porta C, Comolli R (1997) PKC-dependent modulation of IkB alpha-NFkB pathway in low metastatic B16F1 murine melanoma cells and in highly metastatic BL6 cells. Anticancer Res 18:2591–2597
26.
Lee JW, Cheong IY, Kim HS, Lee JJ, Lee YS, Kwon YS, Kim MJ, Lee HJ, Kim SS, Chun W (2011) Anti-inflammatory activity of 1-docosanoyl cafferate isolated from Rhus verniciflua in LPS-stimulated BV2 microglial cells. Korean J Physiol Pharmacol 15:9–15CrossRefPubMedPubMedCentral
27.
Armstrong L, Jordan N, Millar A (1996) Interleukin 10 (IL-10) regulation of tumour necrosis factor alpha (TNF-alpha) from human alveolar macrophages and peripheral blood monocytes. Thorax 51:143–149CrossRefPubMedPubMedCentral
28.
Smallie T, Ricchetti G, Horwood NJ, Feldmann M, Clark AR, Williams LM (2010) IL-10 inhibits transcription elongation of the human TNF gene in primary macrophages. J Exp Med 207:2081–2088CrossRefPubMedPubMedCentral
29.
Schneider-Poetsch T, Ju J, Eyler DE, Jewett JC, Bhat S, Rawal VH, Green R, Liu JO (2010) Inhibition of eukaryotic translation elongation by cycloheximide and lactimidomycin. Nat Chem Biol 6:209–217CrossRefPubMedPubMedCentral
30.
Leclerc GJ, Leclerc GM, Barredo JC (2002) Real-time RT-PCR analysis of mRNA decay: half-life of Beta-actin mRNA in human leukemia CCRF-CEM and Nalm-6 cell lines. Cancer Cell Int 2:1CrossRefPubMedPubMedCentral
31.
Weidensdorfer D, Stöhr N, Baude A, Lederer M, Köhn M, Schierhorn A, Buchmeier S, Wahle E, Hüttelmaier S (2009) Control of c-myc mRNA stability by IGF2BP1-associated cytoplasmic RNPs. RNA 15:104–115CrossRefPubMedPubMedCentral
32.
Hur GM, Hwang YB, Lee JH, Bae SH, Park JS, Lee CJ, Seok JH (2003) Caffeic acid phenethyl ester inhibits the PKC-induced IL-6 gene expression in the synoviocytes of rheumatoid arthritis patients. Korean J Physiol Pharmacol 7:363–368
33.
Chen X, Yang L, Oppenheim JJ, Howard O (2002) Cellular pharmacology studies of shikonin derivatives. Phytother Res 16:199–209CrossRefPubMed
34.
Bai GZ, Yu HT, Ni YF, Li XF, Zhang ZP, Su K, Lei J, Liu BY, Ke CK, Zhong DX (2013) Shikonin attenuates lipopolysaccharide-induced acute lung injury in mice. J Surg Res 182:303–311CrossRefPubMed
35.
Alsaleh G, Suffert G, Semaan N, Juncker T, Frenzel L, Gottenberg JE, Sibilia J, Pfeffer S, Wachsmann D (2009) Bruton’s tyrosine kinase is involved in miR-346-related regulation of IL-18 release by lipopolysaccharide-activated rheumatoid fibroblast-like synoviocytes. J Immunol 182:5088–5097CrossRefPubMed
36.
Philippe L, Alsaleh G, Pichot A, Ostermann E, Zuber G, Frisch B, Sibilia J, Pfeffer S, Bahram S, Wachsmann D (2013) MiR-20a regulates ASK1 expression and TLR4-dependent cytokine release in rheumatoid fibroblast-like synoviocytes. Ann Rheum Dis 72:1071–1079CrossRefPubMed
37.
Chomarat P, Vannier E, Dechanet J, Rissoan MC, Banchereau J, Dinarello CA, Miossec P (1995) Balance of IL-1 receptor antagonist/IL-1 beta in rheumatoid synovium and its regulation by IL-4 and IL-10. J Immunol 154:1432–1439PubMed
38.
Hart P, Ahern M, Smith M, Finlay-Jones J (1995) Comparison of the suppressive effects of interleukin-10 and interleukin-4 on synovial fluid macrophages and blood monocytes from patients with inflammatory arthritis. Immunology 84:536PubMedPubMedCentral
39.
Hart PH, Hunt EK, Bonder CS, Watson CJ, Finlay-Jones JJ (1996) Regulation of surface and soluble TNF receptor expression on human monocytes and synovial fluid macrophages by IL-4 and IL-10. J Immunol 157:3672–3680PubMed
40.
Oswald IP, Wynn TA, Sher A, James SL (1992) Interleukin 10 inhibits macrophage microbicidal activity by blocking the endogenous production of tumor necrosis factor alpha required as a costimulatory factor for interferon gamma-induced activation. Proc Natl Acad Sci USA 89:8676–8680CrossRefPubMedPubMedCentral
41.
Chernoff AE, Granowitz EV, Shapiro L, Vannier E, Lonnemann G, Angel JB, Kennedy JS, Rabson AR, Wolff SM, Dinarello CA (1995) A randomized, controlled trial of IL-10 in humans. Inhibition of inflammatory cytokine production and immune responses. J Immunol 154:5492–5499PubMed
42.
43.
Matsusaka T, Fujikawa K, Nishio Y, Mukaida N, Matsushima K, Kishmoto T, Akira S (1993) Transcription factors NF-IL6 and NF-kappa B synergistically activate transcription of the inflammatory cytokines, interleukin 6 and interleukin 8. Proc Natl Acad Sci USA 90:10193–10197CrossRefPubMedPubMedCentral
44.
45.
Leghmari K, Bennasser Y, Bahraoui E (2008) HIV-1 Tat protein induces IL-10 production in monocytes by classical and alternative NF-κB pathways. Eur J Cell Biol 87:947–962CrossRefPubMed
46.
Correa F, Hernangomez M, Mestre L, Loria F, Spagnolo A, Docagne F, Di Marzo V, Guaza C (2010) Anandamide enhances IL-10 production in activated microglia by targeting CB(2) receptors: roles of ERK1/2, JNK, and NF-kappaB. Glia 58:135–147CrossRefPubMed
47.
Zhang J, Ping P, Vondriska TM, Tang XL, Wang GW, Cardwell EM, Bolli R (2003) Cardioprotection involves activation of NF-kappa B via PKC-dependent tyrosine and serine phosphorylation of I kappa B-alpha. Am J Physiol Heart Circ Physiol 285:H1753–H1758CrossRefPubMed
Metadata
Title
Shikonin inhibits TNF-α production through suppressing PKC-NF-κB-dependent decrease of IL-10 in rheumatoid arthritis-like cell model
Authors
Wen-Xiao Sun
Yan Liu
Wei Zhou
He-Wei Li
Jian Yang
Zhen-Bing Chen
Publication date
01-04-2017
Publisher
Springer Japan
Published in
Journal of Natural Medicines / Issue 2/2017
Print ISSN: 1340-3443
Electronic ISSN: 1861-0293
DOI
https://doi.org/10.1007/s11418-016-1064-3

Other articles of this Issue 2/2017

Journal of Natural Medicines 2/2017 Go to the issue

Original Paper

Koumine exhibits anxiolytic properties without inducing adverse neurological effects on functional observation battery, open-field and Vogel conflict tests in rodents

Original Paper

A novel lectin from Artocarpus lingnanensis induces proliferation and Th1/Th2 cytokine secretion through CD45 signaling pathway in human T lymphocytes

Original Paper

Partial contribution of Rho-kinase inhibition to the bioactivity of Ganoderma lingzhi and its isolated compounds: insights on discovery of natural Rho-kinase inhibitors

Original Paper

Effects of oleuropein on pentylenetetrazol-induced seizures in mice: involvement of opioidergic and nitrergic systems

Original Paper

Antidepressant-like effects of ginsenoside Rg3 in mice via activation of the hippocampal BDNF signaling cascade

Original Paper

p-Hydroxyacetophenone suppresses nuclear factor-κB-related inflammation in nociceptive and inflammatory animal models