PMID- 17530707 OWN - NLM STAT- MEDLINE DCOM- 20070720 LR - 20220224 IS - 0004-3591 (Print) IS - 0004-3591 (Linking) VI - 56 IP - 6 DP - 2007 Jun TI - Interleukin-18 induces angiogenic factors in rheumatoid arthritis synovial tissue fibroblasts via distinct signaling pathways. PG - 1787-97 AB - 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 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. 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-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. CONCLUSION: These 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. FAU - Amin, Mohammad A AU - Amin MA AD - 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 FAU - Mansfield, Pamela J AU - Mansfield PJ FAU - Pakozdi, Angela AU - Pakozdi A FAU - Campbell, Phillip L AU - Campbell PL FAU - Ahmed, Salahuddin AU - Ahmed S FAU - Martinez, Rita J AU - Martinez RJ FAU - Koch, Alisa E AU - Koch AE LA - eng GR - AI-40987/AI/NIAID NIH HHS/United States GR - AR-48267/AR/NIAMS NIH HHS/United States GR - HL-58695/HL/NHLBI NIH HHS/United States GR - R03-AR-052482-01A1/AR/NIAMS NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, Non-U.S. Gov't PT - Research Support, U.S. Gov't, Non-P.H.S. PL - United States TA - Arthritis Rheum JT - Arthritis and rheumatism JID - 0370605 RN - 0 (ATF2 protein, human) RN - 0 (Activating Transcription Factor 2) RN - 0 (Angiogenesis Inducing Agents) RN - 0 (CXCL12 protein, human) RN - 0 (Chemokine CCL2) RN - 0 (Chemokine CXCL12) RN - 0 (Chemokines, CXC) RN - 0 (Interleukin-18) RN - 0 (NF-kappa B) RN - 0 (Vascular Endothelial Growth Factor A) RN - EC 2.7.1.- (Phosphatidylinositol 3-Kinases) RN - EC 2.7.11.13 (Protein Kinase C-delta) RN - EC 2.7.11.24 (p38 Mitogen-Activated Protein Kinases) RN - EC 2.7.12.2 (MAP Kinase Kinase 7) SB - IM MH - Activating Transcription Factor 2/metabolism MH - Angiogenesis Inducing Agents/*metabolism MH - Arthritis, Rheumatoid/*metabolism/pathology MH - Cells, Cultured MH - Chemokine CCL2/genetics/*metabolism MH - Chemokine CXCL12 MH - Chemokines, CXC/genetics/*metabolism MH - Fibroblasts/*metabolism/pathology MH - Humans MH - Interleukin-18/*physiology MH - MAP Kinase Kinase 7/metabolism MH - NF-kappa B/physiology MH - Phosphatidylinositol 3-Kinases/metabolism MH - Protein Kinase C-delta/metabolism MH - Signal Transduction/*physiology MH - Synovial Membrane/metabolism/pathology MH - Up-Regulation MH - Vascular Endothelial Growth Factor A/genetics/*metabolism MH - p38 Mitogen-Activated Protein Kinases/metabolism EDAT- 2007/05/29 09:00 MHDA- 2007/07/21 09:00 CRDT- 2007/05/29 09:00 PHST- 2007/05/29 09:00 [pubmed] PHST- 2007/07/21 09:00 [medline] PHST- 2007/05/29 09:00 [entrez] AID - 10.1002/art.22705 [doi] PST - ppublish SO - Arthritis Rheum. 2007 Jun;56(6):1787-97. doi: 10.1002/art.22705.