Yong-Jin Kwon; Soo-Jin Chung; Tae-Yeon Kim; Min-Chan Park

doi:10.4078/jkra.2010.17.2.153

Journal List > J Korean Rheum Assoc > v.17(2) > 1003715

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Kwon, Chung, Kim, and Park: Peroxisome Proliferator-activated Receptor-γ Agonist Inhibits Pro-inflammatory Gene Expressions and Cellular Proliferation of Fibroblast Like Synoviocytes from Patients with Rheumatoid Arthritis by Down-regulation of NF-kappaB

Original Article

J Korean Rheum Assoc 2010;17(2):153-161.

Published online: 23 June 2010

DOI: https://doi.org/10.4078/jkra.2010.17.2.153

Peroxisome Proliferator-activated Receptor-γ Agonist Inhibits Pro-inflammatory Gene Expressions and Cellular Proliferation of Fibroblast Like Synoviocytes from Patients with Rheumatoid Arthritis by Down-regulation of NF-kappaB

Yong-Jin Kwon, Soo-Jin Chung, Tae-Yeon Kim, Min-Chan Park

Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Korea

Received 3 May 201019 May 2010 Accepted 19 May 2010

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/3.0) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract

Objective

This study investigated the effect of rosiglitazone, a synthetic peroxisome proliferator-activated receptor-γ (PPAR-γ) agonist, on pro-inflammatory gene expressions and cellular proliferation of fibroblast like synoviocyte (FLS) from patients with rheumatoid arthritis (RA), and to determine whether these actions are mediated by nuclear factor-kappaB (NF-B) down-regulation.

Methods

Synovial tissues from patients with RA were obtained during total knee replacement surgery, and FLS were isolated. RA FLS were subsequently treated with 10 μM, 50 μM and 150 μM rosiglitazone with or without TNF-α (10 ng/mL) stimulation. FLS proliferation in response to rosiglitazone treatment was measured by MTT assay, and mRNA expressions of IL-1β, IL-6, CCL-2, CCL-7, COX-2 and MMP-9 were determined by real-time quantitative RT-PCR. The effects of rosiglitazone on NF-κB activation were evaluated using electrophoretic mobility shift assay (EMSA).

Results

Rosiglitazone treatment without TNF-α induced a dose-dependent reduction in mRNA expressions of IL-1β, IL-6, CCL-2, CCL-7, COX-2 and MMP-9 from RA FLS. When TNF-α were treated with rosiglitazone, mRNA expressions of COX-2, MMP-9 were reduced dosedependently. But mRNA expressions of IL-1β, IL-6, CCL-2, CCL-7 were increased in 10 μM rosiglitazone with TNF-α and then decreased as the concentration of rosiglitazone increased. Rosiglitazone treatment also suppressed FLS proliferation in a dose-dependent manner, and EMSA showed decreased NF-κB expression with rosiglitazone treatment.

Conclusion

Rosiglitazone suppressed cellular proliferation and mRNA expressions of pro-inflammatory mediators by down-regulating the NF-κB signaling pathway in RA FLS. The outcomes suggest that activation of PPAR-γ can be a novel therapeutic approach in RA.

Keywords: Rosiglitazone, Rheumatoid arthritis, Fibroblast-like synoviocytes, Pro-inflammatory mediators, NF-κB

REFERENCES

1). Alamanos Y., Voulgari PV., Drosos AA. Incidence and prevalence of rheumatoid arthritis, based on the 1987 American College of Rheumatology criteria: a systematic review. Semin Arthritis Rheum. 2006. 36:182–8.

2). Gabriel SE., Michaud K. Epidemiological studies in incidence, prevalence, mortality, and comorbidity of the rheumatic diseases. Arthritis Res Ther. 2009. 11:229.

3). Lee DM., Weinblatt ME. Rheumatoid arthritis. Lancet. 2001. 358:903–11.

4). Feldmann M., Brennan FM., Maini RN. Rheumatoid arthritis. Cell. 1996. 85:307–10.

5). Arend WP., Dayer JM. Inhibition of the production and effects of interleukin-1 and tumor necrosis factor alpha in rheumatoid arthritis. Arthritis Rheum. 1995. 38:151–60.

6). Dayer JM. The pivotal role of interleukin-1 in the clinical manifestations of rheumatoid arthritis. Rheumatology (Oxford). 2003. ;42 Suppl. 2:3. S.

7). Arend WP., Dayer JM. Cytokines and cytokine inhibitors or antagonists in rheumatoid arthritis. Arthritis Rheum. 1990. 33:305–15.

8). Morand EF., Leech M. Macrophage migration inhibitory factor in rheumatoid arthritis. Front Biosci. 2005. 10:12–22.

9). Sweeney SE., Firestein GS. Rheumatoid arthritis: regulation of synovial inflammation. Int J Biochem Cell Biol. 2004. 36:372–8.

10). Okamoto H., Hoshi D., Kiire A., Yamanaka H., Kamatani N. Molecular targets of rheumatoid arthritis. Inflamm Allergy Drug Targets. 2008. 7:53–66.

11). Simmonds RE., Foxwell BM. Signalling, inflammation and arthritis: NF-kappaB and its relevance to arthritis and inflammation. Rheumatology (Oxford). 2008. 47:584–90.

12). Brown KD., Claudio E., Siebenlist U. The roles of the classical and alternative nuclear factor-kappaB pathways: potential implications for autoimmunity and rheumatoid arthritis. Arthritis Res Ther. 2008. 10:212.

13). Pettit AR., Walsh NC., Manning C., Goldring SR., Gravallese EM. RANKL protein is expressed at the pannus-bone interface at sites of articular bone erosion in rheumatoid arthritis. Rheumatology (Oxford). 2006. 45:1068–76.

14). .

15). .

16). Schoels M., Knevel R., Aletaha D., Bijlsma JW., Breedveld FC., Boumpas DT, et al. Evidence for treating rheumatoid arthritis to target: results of a systematic literature search. Ann Rheum Dis. 2010. 69:638–43.

17). Fleischmann R., Stern R., Iqbal I. Anakinra: an inhibitor of IL-1 for the treatment of rheumatoid arthritis. Expert Opin Biol Ther. 2004. 4:1333–44.

18). Evans RM., Barish GD., Wang YX. PPARs and the complex journey to obesity. Nat Med. 2004. 10:355–61.

19). Tontonoz P., Hu E., Spiegelman BM. Stimulation of adipogenesis in fibroblasts by PPAR gamma 2, a lipid-activated transcription factor. Cell. 1994. 79:1147–56.

20). Cuzzocrea S., Pisano B., Dugo L., Ianaro A., Maffia P., Patel NS, et al. Rosiglitazone, a ligand of the peroxisome proliferator-activated receptor-gamma, reduces acute inflammation. Eur J Pharmacol. 2004. 483:79–93.

21). Saubermann LJ., Nakajima A., Wada K., Zhao S., Terauchi Y., Kadowaki T, et al. Peroxisome proliferator-activated receptor gamma agonist ligands stimulate a Th2 cytokine response and prevent acute colitis. Inflamm Bowel Dis. 2002. 8:330–9.

22). Ricote M., Li AC., Willson TM., Kelly CJ., Glass CK. The peroxisome proliferator-activated receptor-gamma is a negative regulator of macrophage activation. Nature. 1998. 391:79–82.

23). Jiang C., Ting AT., Seed B. PPAR-gamma agonists inhibit production of monocyte inflammatory cytokines. Nature. 1998. 391:82–6.

24). Arnett FC., Edworthy SM., Bloch DA., McShane DJ., Fries JF., Cooper NS, et al. The American Rheumatism Association 1987 revised criteria for the classification of rheumatoid arthritis. Arthritis Rheum. 1988. 31:315–24.

25). Smeets TJ., Dolhain R., Miltenburg AM., de Kuiper R., Breedveld FC., Tak PP. Poor expression of T cell-derived cytokines and activation and proliferation markers in early rheumatoid synovial tissue. Clin Immunol Immunopathol. 1998. 88:84–90.

26). Yamanishi Y., Firestein GS. Pathogenesis of rheumatoid arthritis: the role of synoviocytes. Rheum Dis Clin North Am. 2001. 27:355–71.

27). Iwamoto T., Okamoto H., Toyama Y., Momohara S. Molecular aspects of rheumatoid arthritis: chemokines in the joints of patients. FEBS J. 2008. 275:4448–55.

28). Firestein GS. Evolving concepts of rheumatoid arthritis. Nature. 2003. 423:356–61.

29). Issemann I., Green S. Activation of a member of the steroid hormone receptor superfamily by peroxisome proliferators. Nature. 1990. 347:645–50.

30). Barish GD., Downes M., Alaynick WA., Yu RT., Ocampo CB., Bookout AL, et al. A nuclear receptor atlas: macrophage activation. Mol Endocrinol. 2005. 19:2466–77.

31). Nencioni A., Wesselborg S., Brossart P. Role of peroxisome proliferator-activated receptor gamma and its ligands in the control of immune responses. Crit Rev Immunol. 2003. 23:1–13.

32). Kliewer SA., Forman BM., Blumberg B., Ong ES., Borgmeyer U., Mangelsdorf DJ, et al. Differential expression and activation of a family of murine peroxisome proliferator-activated receptors. Proc Natl Acad Sci U S A. 1994. 91:7355–9.

33). Forman BM., Tontonoz P., Chen J., Brun RP., Spiegelman BM., Evans RM. 15-Deoxy-delta 12, 14-prostaglandin J2 is a ligand for the adipocyte determination factor PPAR gamma. Cell. 1995. 83:803–12.

34). Nagy L., Tontonoz P., Alvarez JG., Chen H., Evans RM. Oxidized LDL regulates macrophage gene expression through ligand activation of PPARgamma. Cell. 1998. 93:229–40.

35). Lehmann JM., Moore LB., Smith-Oliver TA., Wilkison WO., Willson TM., Kliewer SA. An antidiabetic thiazolidinedione is a high affinity ligand for peroxisome proliferator-activated receptor gamma (PPAR gamma). J Biol Chem. 1995. 270:12953–6.

36). Kawahito Y., Kondo M., Tsubouchi Y., Hashiramoto A., Bishop-Bailey D., Inoue K, et al. 15-deoxy-delta (12, 14)-PGJ (2) induces synoviocyte apoptosis and suppresses adjuvant-induced arthritis in rats. J Clin Invest. 2000. 106:189–97.

37). Ji JD., Cheon H., Jun JB., Choi SJ., Kim YR., Lee YH, et al. Effects of peroxisome proliferator-activated receptor-gamma (PPAR-gamma) on the expression of inflammatory cytokines and apoptosis induction in rheumatoid synovial fibroblasts and monocytes. J Autoimmun. 2001. 17:215–21.

38). Han Z., Boyle DL., Manning AM., Firestein GS. AP-1 and NF-kappaB regulation in rheumatoid arthritis and murine collagen-induced arthritis. Autoimmunity. 1998. 28:197–208.

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