Antonelli Alessandro, Ferrari Silvia Martina, Fallahi Poupak, Frascerra Silvia, Santini Eleonora, Franceschini Stefano Sellari, Ferrannini Ele
Department of Internal Medicine, University of Pisa-School of Medicine, Via Roma, 67, I-56100 Pisa, Italy.
J Clin Endocrinol Metab. 2009 May;94(5):1803-9. doi: 10.1210/jc.2008-2450. Epub 2009 Mar 10.
CXC alpha-chemokine CXCL10/IP-10 plays an important role in the initial phases of Graves' ophthalmopathy (GO). Human thyrocytes, orbital fibroblasts, and preadipocytes are stimulated to produce CXCL10 when treated with interferon gamma (IFNgamma) and TNFalpha. Peroxisome proliferator-activated receptor-gamma (PPARgamma) activation plays an inhibitory role in this process.
Until now, no data are present in literature about the involvement of CXCL9 and CXCL11 in Graves' disease and GO, or of PPARgamma activators' effect on these chemokines.
It has been studied how IFNgamma and TNFalpha stimulation and PPARgamma activation affect CXCL9 and CXCL11 secretion in primary cultures of thyrocytes, orbital fibroblasts, and preadipocytes.
In primary cultures of thyrocytes, retrobulbar fibroblasts, and retrobulbar preadipocytes obtained from GO patients, CXCL9 and CXCL11 production was absent under basal conditions; CXCL9 and CXCL11 secretion was not induced by TNFalpha alone, whereas it was dose dependently stimulated treating cells with IFNgamma. The treatment with TNFalpha plus IFNgamma has a synergistic effect on CXCL9 and CXCL11 release. Treating all cell types with the PPARgamma agonist, rosiglitazone, or pioglitazone, the IFNgamma plus TNFalpha-induced CXCL9 and CXCL11 release was dose dependently (0.1-20 microm) suppressed.
We conclude that thyrocytes and retrobulbar cell types from patients with Graves' disease and ophthalmopathy participate in the self-perpetuation of inflammation, releasing CXCL9 and CXCL11 chemokines when stimulated with cytokines. PPARgamma activation plays an inhibitory role in this process. The huge response of CXCL9 to the IFNgamma plus TNFalpha-stimulation suggests its leading role among CXC chemokines.
CXCα趋化因子CXCL10/IP-10在格雷夫斯眼病（GO）的初始阶段起重要作用。人甲状腺细胞、眼眶成纤维细胞和前脂肪细胞在用干扰素γ（IFNγ）和肿瘤坏死因子α（TNFα）处理时会被刺激产生CXCL10。过氧化物酶体增殖物激活受体γ（PPARγ）的激活在此过程中起抑制作用。
迄今为止，尚无关于CXCL9和CXCL11参与格雷夫斯病和GO的数据，也没有关于PPARγ激活剂对这些趋化因子影响的数据。
研究了IFNγ和TNFα刺激以及PPARγ激活如何影响甲状腺细胞、眼眶成纤维细胞和前脂肪细胞原代培养物中CXCL9和CXCL11的分泌。
在从GO患者获得的甲状腺细胞、球后成纤维细胞和球后前脂肪细胞的原代培养物中，基础条件下不产生CXCL9和CXCL11；单独的TNFα不诱导CXCL9和CXCL11分泌，而用IFNγ处理细胞可剂量依赖性地刺激其分泌。TNFα加IFNγ处理对CXCL9和CXCL11的释放有协同作用。用PPARγ激动剂罗格列酮或吡格列酮处理所有细胞类型，IFNγ加TNFα诱导的CXCL9和CXCL11释放被剂量依赖性（0.1 - 20微摩尔）抑制。
我们得出结论，格雷夫斯病和眼病患者的甲状腺细胞和球后细胞类型参与炎症的自我持续，在受到细胞因子刺激时释放CXCL9和CXCL11趋化因子。PPARγ激活在此过程中起抑制作用。CXCL9对IFNγ加TNFα刺激的巨大反应表明其在CXC趋化因子中起主导作用。
