Up-regulation of stromal cell-derived factor by il-17 and il-18 via PI3K dependent pathway.

Abstract

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.