Peroxisome Proliferator-activated Receptor γ Ligands Inhibit Transforming Growth Factor-β-induced, Hyaluronan-dependent, T Cell Adhesion to Orbital Fibroblasts
Peroxisome Proliferator-activated Receptor γ Ligands Inhibit Transforming Growth Factor-β-induced, Hyaluronan-dependent, T Cell Adhesion to Orbital Fibroblasts
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DOI：
10.1074/jbc.m110.179317
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发表时间：
2011-05-27
影响因子：
4.8
通讯作者：
Phipps, Richard P.
中科院分区：
文献类型：
--
作者：
Guo, Naxin;Woeller, Collynn F.;Phipps, Richard P.
甲状腺眼病的特征是白细胞浸润和透明质酸（HA）在眼眶组织中的积聚。由于过量的HA和瘢痕组织（纤维化）和/或脂肪堆积的形成，发炎的眼眶组织尺寸扩大。转化生长因子β（TGF-β）通过增强细胞外基质产生而充当纤维化的关键诱导剂。用TGF-β处理原代人眼眶成纤维细胞导致HA合成和分泌显著增加。TGF-β还强烈诱导透明质酸合成酶1（HAS 1）和HAS 2 mRNA水平，分别增加50倍和6倍。值得注意的是，在TGF-β处理的眼眶成纤维细胞中加入过氧化物酶体增殖物激活受体（PPAR γ）配体吡格列酮（Pio）或罗格列酮（Rosi）可减弱HA合成，并降低HAS 1和HAS 2 mRNA水平。Pio和Rosi对TGF-β功能的减弱与PPAR γ活性无关。此外，Pio和Rosi处理抑制TGF-β诱导的T细胞粘附到眼眶成纤维细胞。我们的研究结果表明，TGF-β通过增强或促进炎症细胞浸润和粘附到眼眶组织中，在HA合成和炎症反应中起重要作用。Pio和Rosi具有抗纤维化和抗炎活性，可用于治疗甲状腺眼病。
Thyroid eye disease is characterized by the infiltration of leukocytes and accumulation of hyaluronan (HA) in orbital tissue. Inflamed orbital tissue expands in size due to excessive HA and to the formation of scar tissue (fibrosis) and/or adipose accumulation. Transforming growth factor beta (TGF-beta) acts as a key inducer of fibrosis by enhancing extracellular matrix production. Treatment of primary human orbital fibroblasts with TGF-beta led to significant increases in both HA synthesis and secretion. TGF-beta also strongly induced hyaluronan synthase 1 (HAS1) and HAS2 mRNA levels, which increased 50- and 6-fold, respectively. Remarkably, the addition of the peroxisome proliferator-activated receptor (PPAR gamma) ligands pioglitazone (Pio) or rosiglitazone (Rosi) to TGF-beta-treated orbital fibroblasts attenuated HA synthesis and reduced HAS1 and HAS2 mRNA levels. The attenuation of TGF-beta function by Pio and Rosi was independent of PPAR gamma activity. Furthermore, Pio and Rosi treatment inhibited TGF-beta-induced T cell adhesion to orbital fibroblasts. Our findings demonstrate that TGF-beta plays an important role in HA synthesis and in the inflammatory response by enhancing or facilitating inflammatory cell infiltration and adhesion to orbital tissue. Pio and Rosi exhibit anti-fibrotic and anti-inflammatory activity and may be useful in treating thyroid eye disease.