Department of Internal Medicine, University of Michigan Medical School, 109 Zina Pitcher Dr., Ann Arbor, MI 48109, USA.
Arthritis Res Ther. 2011 Feb 8;13(1):R18. doi: 10.1186/ar3242.
Systemic sclerosis (SSc) is characterized by fibrosis and microvascular abnormalities including dysregulated angiogenesis. Chemokines, in addition to their chemoattractant properties, have the ability to modulate angiogenesis. Chemokines lacking the enzyme-linked receptor (ELR) motif, such as monokine induced by interferon-γ (IFN-γ) (MIG/CXCL9) and IFN-inducible protein 10 (IP-10/CXCL10), inhibit angiogenesis by binding CXCR3. In addition, CXCL16 promotes angiogenesis by binding its unique receptor CXCR6. In this study, we determined the expression of these chemokines and receptors in SSc skin and serum.
Immunohistology and enzyme-linked immunosorbent assays (ELISAs) were used to determine chemokine and chemokine receptor expression in the skin and serum, respectively, of SSc and normal patients. Endothelial cells (ECs) were isolated from SSc skin biopsies and chemokine and chemokine receptor expression was determined by quantitative PCR and immunofluorescence staining.
Antiangiogenic IP-10/CXCL10 and MIG/CXCL9 were elevated in SSc serum and highly expressed in SSc skin. However, CXCR3, the receptor for these chemokines, was decreased on ECs in SSc vs. normal skin. CXCL16 was elevated in SSc serum and increased in SSc patients with early disease, pulmonary arterial hypertension, and those that died during the 36 months of the study. In addition, its receptor CXCR6 was overexpressed on ECs in SSc skin. At the mRNA and protein levels, CXCR3 was decreased while CXCR6 was increased on SSc ECs vs. human microvascular endothelial cells (HMVECs).
These results show that while the expression of MIG/CXCL9 and IP-10/CXCL10 are elevated in SSc serum, the expression of CXCR3 is downregulated on SSc dermal ECs. In contrast, CXCL16 and CXCR6 are elevated in SSc serum and on SSc dermal ECs, respectively. In all, these findings suggest angiogenic chemokine receptor expression is likely regulated in an effort to promote angiogenesis in SSc skin.
系统性硬化症（SSc）的特征是纤维化和微血管异常，包括失调的血管生成。趋化因子除了具有趋化作用外，还具有调节血管生成的能力。缺乏酶联受体（ELR）基序的趋化因子，如干扰素-γ（IFN-γ）诱导的单核细胞趋化蛋白-1（MIG/CXCL9）和干扰素诱导蛋白 10（IP-10/CXCL10），通过结合 CXCR3 抑制血管生成。此外，CXCL16 通过与其独特的受体 CXCR6 结合促进血管生成。在这项研究中，我们确定了 SSc 皮肤和血清中这些趋化因子和受体的表达。
免疫组织化学和酶联免疫吸附试验（ELISA）分别用于确定 SSc 和正常患者皮肤和血清中趋化因子和趋化因子受体的表达。从 SSc 皮肤活检中分离出内皮细胞（ECs），通过定量 PCR 和免疫荧光染色确定趋化因子和趋化因子受体的表达。
抗血管生成的 IP-10/CXCL10 和 MIG/CXCL9 在 SSc 血清中升高，并在 SSc 皮肤中高表达。然而，在 SSc 皮肤与正常皮肤的 ECs 上，这些趋化因子的受体 CXCR3 减少。CXCL16 在 SSc 血清中升高，并在 SSc 患者中增加，这些患者在研究的 36 个月内患有早期疾病、肺动脉高压和死亡。此外，其受体 CXCR6 在 SSc 皮肤的 ECs 上过度表达。在 mRNA 和蛋白质水平上，与人类微血管内皮细胞（HMVECs）相比，SSc ECs 上的 CXCR3 减少，而 CXCR6 增加。
这些结果表明，虽然 MIG/CXCL9 和 IP-10/CXCL10 在 SSc 血清中的表达升高，但 SSc 真皮 ECs 上的 CXCR3 表达下调。相比之下，CXCL16 和 CXCR6 分别在 SSc 血清和 SSc 真皮 ECs 中升高。总的来说，这些发现表明，SSc 皮肤中血管生成趋化因子受体的表达可能受到调节，以促进血管生成。
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