Gao Bradley T, Lee Ryan P, Jiang Youde, Steinle Jena J, Morales-Tirado Vanessa M
Department of Ophthalmology, College of Medicine, The University of Tennessee Health Science Center, Memphis, TN 38163 USA.
Department of Ophthalmology, College of Medicine, The University of Tennessee Health Science Center, Memphis, TN 38163 USA ; Department of Anatomy and Neurobiology, College of Medicine, The University of Tennessee Health Science Center, Memphis, TN 38163 USA ; Department of Anatomy and Cell Biology, Wayne State University School of Medicine, Detroit, MI USA.
Diabetol Metab Syndr. 2015 Sep 2;7:72. doi: 10.1186/s13098-015-0068-6. eCollection 2015.
BACKGROUND: Type 2 diabetes is commonly characterized by insulin deficiency and decreased sensitivity of insulin receptors, leading to a chronic state of hyperglycemia in individuals. Disease progression induces changes in the immune profile that engenders a chronic inflammatory condition. Thiazolidinedione (TDZ) drugs, such as Pioglitazone (Pio), aid in controlling disease symptoms. While the mechanisms by which Pio controls hyperglycemia are beginning to be understood, relatively little is known about the effects of Pio on suppression of the systemic immune phenotype, attributed to visceral adipose tissue and macrophages. METHODS: Here, we utilize the recently developed BBDZR/Wor type 2 diabetes rat model to test our hypothesis that a selective in vivo growth of CD3(+)T cells in the spleen contributes to the increase in T lymphocytes, including Tregs, independent of visceral adipose tissue. We investigated the systemic effects of Pio on multifactorial aspects of the disease-induced immune phenotype both in vivo and in vitro in normal, non-diabetic animals and in disease. RESULTS: Our work revealed that Pio reversed the lymphopenic status of diabetic rats, in part by an increase in CD3(+) T lymphocytes and related subsets. Moreover, we found evidence that Pio caused a selective growth of newly differentiated T lymphocytes, based on the presence of recent thymic emigrants in vivo. To investigate effects of Pio on the inflammatory milieu, we examined the production of the signature cytokines TNF-α and IL-1β and found they were reduced by Pio-treatment, while the levels of IL-4, an anti-inflammatory mediator, were significantly increased in a Pio-dependent manner. The increase in IL-4 production, although historically attributed to macrophages from visceral adipose tissue under other conditions, came also from CD3(+) T lymphocytes from the spleen, suggesting splenocytes contribute to the Pio-induced shift towards an anti-inflammatory phenotype. CONCLUSIONS: We show for the first time that Pio treatment significantly suppresses the systemic inflammatory status in the BBDZR/Wor type 2 diabetes rat model by the selective growth of newly differentiated CD3(+) T cells and by increasing CD3(+)IL-4 production in immigrant spleen lymphocytes.
背景：2型糖尿病的常见特征是胰岛素缺乏和胰岛素受体敏感性降低，导致个体长期处于高血糖状态。疾病进展会引起免疫特征的变化，从而引发慢性炎症状态。噻唑烷二酮（TDZ）类药物，如吡格列酮（Pio），有助于控制疾病症状。虽然Pio控制高血糖的机制已开始为人所知，但关于Pio对由内脏脂肪组织和巨噬细胞引起的全身免疫表型抑制作用的了解相对较少。 方法：在此，我们利用最近开发的BBDZR/Wor 2型糖尿病大鼠模型来检验我们的假设，即脾脏中CD3(+)T细胞的选择性体内生长导致包括调节性T细胞（Tregs）在内的T淋巴细胞增加，且与内脏脂肪组织无关。我们在正常、非糖尿病动物以及患病动物体内和体外研究了Pio对疾病诱导的免疫表型多因素方面的全身影响。 结果：我们的研究表明，Pio部分通过增加CD3(+)T淋巴细胞及相关亚群逆转了糖尿病大鼠的淋巴细胞减少状态。此外，基于体内近期胸腺迁出细胞的存在，我们发现有证据表明Pio导致新分化的T淋巴细胞选择性生长。为了研究Pio对炎症环境的影响，我们检测了标志性细胞因子TNF-α和IL-1β的产生，发现Pio治疗可使其降低，而抗炎介质IL-4的水平则以Pio依赖的方式显著增加。IL-4产生的增加，虽然以往在其他条件下被认为是来自内脏脂肪组织的巨噬细胞，但也来自脾脏的CD3(+)T淋巴细胞，这表明脾细胞促成了Pio诱导的向抗炎表型的转变。 结论：我们首次表明，在BBDZR/Wor 2型糖尿病大鼠模型中，Pio治疗通过新分化的CD3(+)T细胞的选择性生长以及脾脏淋巴细胞中CD3(+)IL-4产生的增加，显著抑制了全身炎症状态。
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