Interleukin‐18 induces angiogenic factors in rheumatoid arthritis synovial tissue fibroblasts via distinct signaling pathways

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Abstract
Objective Interleukin-18 (IL-18) is a proinflammatory cytokine implicated in the pathogenesis of rheumatoid arthritis (RA). This study was undertaken to examine the role of IL-18 in up-regulating secretion of the angiogenic factors stromal cell–derived factor 1α (SDF-1α)/CXCL12, monocyte chemoattractant protein 1 (MCP-1)/CCL2, and vascular endothelial growth factor (VEGF) in RA synovial tissue (ST) fibroblasts, and the underlying signaling mechanisms involved. Methods We used enzyme-linked immunosorbent assays, Western blotting, and chemical inhibitors/antisense oligodeoxynucleotides to signaling intermediates to assess the role of IL-18. Results IL-18 significantly enhanced the production of SDF-1α/CXCL12, MCP-1/CCL2, and VEGF in RA ST fibroblasts, in a time- and concentration-dependent manner. IL-18–induced SDF-1α/CXCL12 up-regulation was dependent on JNK, p38 MAPK, phosphatidylinositol 3-kinase (PI3K), and NFκB. While IL-18–induced production of SDF-1α/CXCL12 was also dependent on protein kinase Cδ (PKCδ), production of MCP-1/CCL2 was dependent on PKCα, not PKCδ. Additionally, RA ST fibroblast IL-18–induced MCP-1/CCL2 production was mediated by JNK, PI3K, and NFκB. In contrast, IL-18 did not induce secretion of RA ST fibroblast MCP-1/CCL2 or VEGF via p38 MAPK. IL-18–induced RA ST fibroblast production of VEGF was mediated mainly by JNK-2, PKCα, and NFκB. IL-18 induced phosphorylation of JNK, PKCδ, p38 MAPK, and activating transcription factor 2 (ATF-2) in RA ST fibroblasts in a time-dependent manner, with JNK-2 being upstream of PKCδ, ATF-2, and NFκB. Conclusion These data support the notion that IL-18 has a unique role in inducing the secretion of angiogenic SDF-1α/CXCL12, MCP-1/CCL2, and VEGF in RA ST fibroblasts, via distinct signaling intermediates.