Role of stromal-cell derived factor-1 in the development of autoimmune diseases in non-obese diabetic mice

3046 Background: Stromal cell-derived factor-1 (SDF-1) is a versatile chemotactic cytokine and a sole ligand of CXCR4. SDF-1-CXCR4 axis is the most commonly expressed pathway in cancer cells, and is also responsible for metastasis, homing of stem cell, HIV infection, and autoimmune diseases. Interleukin (IL)-17 plays a key role in the pathogenesis of inflammation by inducing SDF-1 to propagate inflammation and vascular endothelial growth factor to provoke angiogenesis. Recent studies revealed that IL-17 pathway is interwoven with multiple cytokines and downstream pathways. Members of the IL-1β family, including IL-18, have recently gained attention. By measuring SDF-1 production regulated by individual and simultaneous cytokine stimulations, two cytokines were explored to define their effects, their downstream signal transduction pathways, and the impact of their antibodies. Methods: Synovial tissue was obtained from patients with rheumatoid arthritis and their age- and sex-matched controls with osteoarthritis. Fibroblast-like synoviocytes (FLS) were isolated and stimulated with a combination of IL-17 and IL-18 and quantified SDF-1 production with ELISA and their transcripts with RT-PCR. Another subset of FLS were preconditioned with PI3K inhibitor, 100 nM wortmannin, and stimulated with either 5 ng/mL of IL-17, 10 ng/mL of IL-18, or combination of both cytokines. Mann-Whitney test was adopted for statistical analysis. Results: Both IL-17 and IL-18 increased SDF-1 level and its mRNA transcript, not only individually but also synergistically (p <0.05). In the group where PI3K inihibitor was applied, the individual and synergistic promotion of SDF-1 production by IL-17 and IL-18 were inhibited (p<0.05). Concomitant application of anti-IL-17 and anti-IL-18 led to further decline of SDF-1 production (p<0.01). Conclusions: This is the first report of PI3K-dependent synergism between IL-18 and IL-17, and adds a novel perspective of the role of IL-18 in immune regulation. The individual effects of these two cytokines, and their interaction through PI3K, suggest an interrelationship between the IL-1 family and IL-17.

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Abstract 279: Stromal Cell-derived Factor-1 Prevents From Diabetic Cardiomyopathy via Cxcr7/ampk-mediated Nrf2 Activation in Type 2 Diabetic Mice

Circulation Research ◽

10.1161/res.119.suppl_1.279 ◽

2016 ◽

Vol 119 (suppl_1) ◽

Author(s):

Shudong Wang ◽

Junlian Gu ◽

Xiaoqing Yan ◽

Jing Chen ◽

Jun Chen ◽

...

Keyword(s):

Insulin Resistance ◽

Blood Glucose ◽

Cardiac Function ◽

Stromal Cell ◽

Normal Diet ◽

Diabetic Mice ◽

Nrf2 Activation ◽

Stromal Cell Derived Factor ◽

Type 2 Diabetic

We have demonstrated that stromal cell-derived factor 1(SDF-1) protects against palmitate-induced cardiac cell death via CXCR7-mediated activation of AMPK signaling (Diabetes 62:2545-2558, 2013). Whether SDF-1 prevents diabetic cardiomyopathy (DCM) and what the underlying mechanism has not been addressed. Here we evaluated the prevention of SDF-1 from DCM in a high fat diet plus streptozotocin (HFD/STZ)-induced type 2 diabetic model in C57BL/6J mice. After 1 month on HFD, the HFD-fed mice were injected with one low dose STZ (100mg/kg body weight, ip). Five days after STZ injection, mice with blood glucose levels ≥250 mg/dl were defined as diabetic. In parallel, the age-matched normal diet-fed mice injected with a same volume of vehicle were used as control. After onset of diabetes, the mice were maintained on HFD or normal diet for another 4 months with or without SDF-1 treatment. Then cardiac function was assayed again, and the mice were sacrificed and cardiac tissue collected for cardiomyopathic index assay. We found that 1 month HFD feeding induced a significant insulin resistance without effect on cardiac function, but continued HFD feeding after STZ injection significantly increased insulin resistance and blood glucose, as well as blood insulin, triglyceride and cholesterol levels. Furthermore, HFD/STZT significantly impaired cardiac function, which were accompanied by increased cardiac inflammation, oxidative stress and fibrotic remodeling. Treatment with SDF-1 dose-dependently prevented diabetes-induced cardiac dysfunction, inflammation and remodeling, but without significant effects on the above mentioned other pathophysiological changes. Mechanistic study demonstrated that diabetes significantly inhibited the function of AMPK and Nrf2, and the expression of CXCR7, but not CXCR4; while treatment with SDF-1 significantly preserved AMPK and Nrf2 function and CXCR7 expression. Knockout CXCR4 did not affect SDF-1 preservation of AMPK and Nrf2 function, but SiRNA knockdown of AMPK resulted in blockade of SDF-1 preservation of Nrf2 function. These results indicate that SDF-1 prevents from DCM via CXCR7/AMPK-mediated Nrf2 activation in type 2 diabetic mice.

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