PPARγ ligands inhibit nitrotyrosine formation and inflammatory mediator expressions in adjuvant-induced rheumatoid arthritis mice
Introduction
Many reports indicated formation of nitrotyrosine in proteins during inflammation such as arthritis, nephritis, sepsis and ischemia–reperfusion injury, because nitrotyrosine is formed by a reaction of tyrosine residue with peroxynitrite generated from superoxide and nitric oxide (NO) radicals Wada et al., 1998, Mapp et al., 2001, Noiri et al., 2001, Pfeiffer et al., 2001. Pathological roles of nitrotyrosine are still unknown. However, it is required for normal physiological conditions to reduce or metabolize the nitrated proteins, since the nitrated proteins may affect physiological regulation systems by phosphorylation of tyrosine. Few reports indicated inhibitors on the formation of nitrotyrosine, although there might be specific enzymes that recover function of the nitrated proteins (Kamisaki et al., 1998).
Peroxisome proliferator-activated receptor gamma (PPARγ) is a member of nuclear receptor superfamily of ligand-activated transcriptional factors including steroid hormone, thyroid hormone, vitamin D, and retinoic acid Michalik and Wahli, 1999, Kersten et al., 2000. PPARγ is highly expressed in adipose tissue and plays a key role in adipocyte differentiation and insulin sensitivity. Synthesized ligands, thiazolidinedione derivatives, such as rosiglitazone, pioglitazone and troglitazone, are used as oral antihyperglycemic agents in the therapy of non-insulin-dependent diabetes mellitus Vamecq and Latruffe, 1999, Kadowaki, 2000. In addition, recent studies have shown that PPARγ may participate in control of inflammation, especially, in modulating the production of inflammatory mediators Jiang et al., 1998, Ricote et al., 1998. Actually, we have reported that the stimulation of endogenous PPARγ pathway causes anti-inflammatory responses in experimental bowel disease inflammation, such as dextran sodium sulfate and ischemia-induced colitis Nakajima et al., 2001, Saubermann et al., 2001, Wada et al., 2001. According to those observations, PPARγ ligand therapy is also suggested to suppress other inflammatory diseases such as rheumatoid arthritis, sepsis, nephritis and pancreatitis.
Rheumatoid arthritis is a chronic, destructive polyarticular joint disease, being characterized massive synovial proliferation and subintimal infiltration of inflammatory cells (Feldmann, 2001). In this report, we applied PPARγ specific ligands, rosiglitazone and pioglitazone, for adjuvant-induced murine arthritis model. We investigated the effects of PPARγ ligands on the nitrotyrosine formation and inflammatory mediator expression, such as inducible nitric oxide (iNOS), cyclooxygenase-2 and intercellular adhesion molecule-1 (ICAM-1), in ankle and temporomandibular joint tissues. First, we revealed that administration of PPARγ ligands inhibits expression of inflammatory mediators in arthritis tissues, and that suppression of nuclear factor (NF)-κB pathway may be involved in the inhibitory mechanisms of PPARγ ligands on the nitrotyrosine formation and inflammatory mediator expressions in ankle and temporomandibular joints.
Section snippets
Adjuvant-induced arthritis
All animal experiments were performed in accordance with the guideline for animal experimentation of Graduate School of Dentistry, Osaka University. Adult male Balb/c mice were purchased from SLC (Shizuoka, Japan). Under slight ether anesthesia, adjuvant-induced arthritis was induced by injection of complete Freund's adjuvant (CFA, Difco Laboratories; 0.2 ml 1:1 saline suspension) in mice back skin (Nozawa-Inoue et al., 1998). The animals were sacrificed, Ankle and temporomandibular joints were
PPARγ ligands inhibit adjuvant-induced nitrotyrosine formation in joint tissues
Administration of adjuvant (CFA) increased nitrotyrosine formation in ankle and temporomandibular joints (Fig. 1). By Western blot analysis, although several proteins of various molecular weights were nitrated, the protein of 90–100 kDa is most extensively nitrated (shown in Fig. 1A and B, respectively). Normalized net band intensities of nitrated proteins were also shown in Fig. 1C and D, respectively. We also confirmed the formation of nitrotyrosine in CFA-treated mice by immunohistochemical
Discussion
It is well known that superoxide and NO radicals rapidly react with each other to form peroxynitrite, and the peroxynitrite attacks to tyrosine residues in proteins, resulting in the formation of nitrotyrosine residues in proteins Xia and Zweier, 1997, Greenacre and Ischiropoulos, 2001, Knapp et al., 2001. Therefore, increased nitrotyrosine formation is due to a result of inflammation Kamisaki et al., 1997, Wada et al., 1998, Greenacre and Ischiropoulos, 2001, Mapp et al., 2001. In this study,
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