• Mohammad A Amin, Pamela J Mansfield, Angela Pakozdi, Phillip L Campbell, Salahuddin Ahmed, Rita J Martinez, and Alisa E Koch.
• Department of Internal Medicine, Division of Rheumatology, University of Michigan Medical School, University of Michigan Health System, Ann Arbor, MI, USA. maamin@med.umich.edu
• Arthritis Rheum. 2007 Jun 1; 56 (6): 1787-97.

ObjectiveInterleukin-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 1alpha (SDF-1alpha)/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.MethodsWe used enzyme-linked immunosorbent assays, Western blotting, and chemical inhibitors/antisense oligodeoxynucleotides to signaling intermediates to assess the role of IL-18.ResultsIL-18 significantly enhanced the production of SDF-1alpha/CXCL12, MCP-1/CCL2, and VEGF in RA ST fibroblasts, in a time- and concentration-dependent manner. IL-18-induced SDF-1alpha/CXCL12 up-regulation was dependent on JNK, p38 MAPK, phosphatidylinositol 3-kinase (PI3K), and NFkappaB. While IL-18-induced production of SDF-1alpha/CXCL12 was also dependent on protein kinase Cdelta (PKCdelta), production of MCP-1/CCL2 was dependent on PKCalpha, not PKCdelta. Additionally, RA ST fibroblast IL-18-induced MCP-1/CCL2 production was mediated by JNK, PI3K, and NFkappaB. 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, PKCalpha, and NFkappaB. IL-18 induced phosphorylation of JNK, PKCdelta, p38 MAPK, and activating transcription factor 2 (ATF-2) in RA ST fibroblasts in a time-dependent manner, with JNK-2 being upstream of PKCdelta, ATF-2, and NFkappaB.ConclusionThese data support the notion that IL-18 has a unique role in inducing the secretion of angiogenic SDF-1alpha/CXCL12, MCP-1/CCL2, and VEGF in RA ST fibroblasts, via distinct signaling intermediates.

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