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

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 la (SDF-1 alpha)/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-1 alpha/CXCL12, MCP-1/CCL2, and VEGF in RA ST fibroblasts, in a time- and concentration-dependent manner. IL-18-induced SDF-1a/CXCL12 up-regulation was dependent on JNK, p38 MAPK, phosphatidylinositol 3-kinase (PI3K), and NF kappa B. While IL-18-induced production of SDF-1a/CXCL12 was also dependent on protein kinase CS (PKC delta), production of MCP-1/CCL2 was dependent on PKC alpha, not PKC delta. Additionally, RA ST fibroblast IL-18-induced MCP-1/ CCL2 production was mediated by JNK, PI3K, and NF kappa B 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, PKC alpha, and NF kappa B. IL-18 induced phosphorylation of JNK, PKCS, p38 MAPK, and activating transcription factor 2 (ATF-2) in RA ST fibroblasts in,a time-dependent manner, with JNK-2 being upstream of PKCS, ATF-2, and NF kappa B. Conclusion. These data support the notion that IL-18 has a unique role in inducing the secretion of angiogenic SDF-1 alpha/CXCL12, MCP-1/CCL2, and VEGF in RA ST fibroblasts, via distinct signaling intermediates.