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PLOS ONE  2012 

The CCL2/CCR2 Axis Enhances Vascular Cell Adhesion Molecule-1 Expression in Human Synovial Fibroblasts

DOI: 10.1371/journal.pone.0049999

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Background Chemokine ligand 2 (CCL2), also known as monocyte chemoattractant protein-1 (MCP-1), belongs to the CC chemokine family that is associated with the disease status and outcomes of osteoarthritis (OA). Here, we investigated the intracellular signaling pathways involved in CCL2-induced vascular cell adhesion molecule-1 (VCAM-1) expression in human OA synovial fibroblasts (OASFs). Methodology/Principal Findings Stimulation of OASFs with CCL2 induced VCAM-1 expression. CCL2-mediated VCAM-1 expression was attenuated by CCR2 inhibitor (RS102895), PKCδ inhibitor (rottlerin), p38MAPK inhibitor (SB203580), and AP-1 inhibitors (curcumin and tanshinone IIA). Stimulation of cells with CCL2 increased PKCδ and p38MAPK activation. Treatment of OASFs with CCL2 also increased the c-Jun phosphorylation and c-Jun binding to the AP-1 element on the VCAM-1 promoter. Moreover, CCL2-mediated CCR2, PKCδ, p38MAPK, and AP-1 pathway promoted the adhesion of monocytes to the OASFs monolayer. Conclusions/Significance Our results suggest that CCL2 increases VCAM-1 expression in human OASFs via the CCR2, PKCδ, p38MAPK, c-Jun, and AP-1 signaling pathway. The CCL2-induced VCAM-1 expression promoted monocytes adhesion to human OASFs.


[1]  Mor A, Abramson SB, Pillinger MH (2005) The fibroblast-like synovial cell in rheumatoid arthritis: a key player in inflammation and joint destruction. Clin Immunol 115: 118–128.
[2]  Shen PC, Wu CL, Jou IM, Lee CH, Juan HY, et al. (2011) T helper cells promote disease progression of osteoarthritis by inducing macrophage inflammatory protein-1gamma. Osteoarthritis and cartilage/OARS, Osteoarthritis Research Society 19: 728–736.
[3]  Choy EH, Panayi GS (2001) Cytokine pathways and joint inflammation in rheumatoid arthritis. The New England journal of medicine 344: 907–916.
[4]  Sakkas LI, Platsoucas CD (2007) The role of T cells in the pathogenesis of osteoarthritis. Arthritis and rheumatism 56: 409–424.
[5]  Sucosky P, Balachandran K, Elhammali A, Jo H, Yoganathan AP (2009) Altered shear stress stimulates upregulation of endothelial VCAM-1 and ICAM-1 in a BMP-4- and TGF-beta1-dependent pathway. Arterioscler Thromb Vasc Biol 29: 254–260.
[6]  Qureshi MH, Cook-Mills J, Doherty DE, Garvy BA (2003) TNF-alpha-dependent ICAM-1- and VCAM-1-mediated inflammatory responses are delayed in neonatal mice infected with Pneumocystis carinii. J Immunol 171: 4700–4707.
[7]  Schett G, Kiechl S, Bonora E, Zwerina J, Mayr A, et al. (2009) Vascular cell adhesion molecule 1 as a predictor of severe osteoarthritis of the hip and knee joints. Arthritis Rheum 60: 2381–2389.
[8]  Kalichman L, Pantsulaia I, Kobyliansky E (2011) Association between vascular cell adhesion molecule 1 and radiographic hand osteoarthritis. Clin Exp Rheumatol 29: 544–546.
[9]  Karatay S, Kiziltunc A, Yildirim K, Karanfil RC, Senel K (2004) Effects of different hyaluronic acid products on synovial fluid levels of intercellular adhesion molecule-1 and vascular cell adhesion molecule-1 in knee osteoarthritis. Ann Clin Lab Sci 34: 330–335.
[10]  Szekanecz Z, Kim J, Koch AE (2003) Chemokines and chemokine receptors in rheumatoid arthritis. Seminars in immunology 15: 15–21.
[11]  Maghazachi AA, al-Aoukaty A, Schall TJ (1994) C-C chemokines induce the chemotaxis of NK and IL-2-activated NK cells. Role for G proteins. Journal of immunology 153: 4969–4977.
[12]  Koch AE, Kunkel SL, Harlow LA, Johnson B, Evanoff HL, et al. (1992) Enhanced production of monocyte chemoattractant protein-1 in rheumatoid arthritis. The Journal of clinical investigation 90: 772–779.
[13]  Levinger I, Levinger P, Trenerry MK, Feller JA, Bartlett JR, et al. (2011) Increased inflammatory cytokine expression in the vastus lateralis of patients with knee osteoarthritis. Arthritis and rheumatism 63: 1343–1348.
[14]  Akahoshi T, Wada C, Endo H, Hirota K, Hosaka S, et al. (1993) Expression of monocyte chemotactic and activating factor in rheumatoid arthritis. Regulation of its production in synovial cells by interleukin-1 and tumor necrosis factor. Arthritis and rheumatism 36: 762–771.
[15]  Gong JH, Ratkay LG, Waterfield JD, Clark-Lewis I (1997) An antagonist of monocyte chemoattractant protein 1 (MCP-1) inhibits arthritis in the MRL-lpr mouse model. The Journal of experimental medicine 186: 131–137.
[16]  Eisinger K, Bauer S, Schaffler A, Walter R, Neumann E, et al. (2012) Chemerin induces CCL2 and TLR4 in synovial fibroblasts of patients with rheumatoid arthritis and osteoarthritis. Experimental and molecular pathology 92: 90–96.
[17]  Juarranz Y, Gutierrez-Canas I, Santiago B, Carrion M, Pablos JL, et al. (2008) Differential expression of vasoactive intestinal peptide and its functional receptors in human osteoarthritic and rheumatoid synovial fibroblasts. Arthritis and rheumatism 58: 1086–1095.
[18]  Tang CH, Chiu YC, Tan TW, Yang RS, Fu WM (2007) Adiponectin enhances IL-6 production in human synovial fibroblast via an AdipoR1 receptor, AMPK, p38, and NF-kappa B pathway. Journal of immunology 179: 5483–5492.
[19]  Tang CH, Hsu CJ, Fong YC (2010) The CCL5/CCR5 axis promotes interleukin-6 production in human synovial fibroblasts. Arthritis and rheumatism 62: 3615–3624.
[20]  Hsieh MT, Hsieh CL, Lin LW, Wu CR, Huang GS (2003) Differential gene expression of scopolamine-treated rat hippocampus-application of cDNA microarray technology. Life sciences 73: 1007–1016.
[21]  Wang YC, Lee PJ, Shih CM, Chen HY, Lee CC, et al. (2003) Damage formation and repair efficiency in the p53 gene of cell lines and blood lymphocytes assayed by multiplex long quantitative polymerase chain reaction. Analytical biochemistry 319: 206–215.
[22]  Huang HC, Shi GY, Jiang SJ, Shi CS, Wu CM, et al. (2003) Thrombomodulin-mediated cell adhesion: involvement of its lectin-like domain. The Journal of biological chemistry 278: 46750–46759.
[23]  Tseng CP, Huang CL, Huang CH, Cheng JC, Stern A, et al. (2003) Disabled-2 small interfering RNA modulates cellular adhesive function and MAPK activity during megakaryocytic differentiation of K562 cells. FEBS letters 541: 21–27.
[24]  Lin WN, Luo SF, Lin CC, Hsiao LD, Yang CM (2009) Differential involvement of PKC-dependent MAPKs activation in lipopolysaccharide-induced AP-1 expression in human tracheal smooth muscle cells. Cell Signal 21: 1385–1395.
[25]  Aragay AM, Mellado M, Frade JM, Martin AM, Jimenez-Sainz MC, et al. (1998) Monocyte chemoattractant protein-1-induced CCR2B receptor desensitization mediated by the G protein-coupled receptor kinase 2. Proceedings of the National Academy of Sciences of the United States of America 95: 2985–2990.
[26]  Zhang T, Somasundaram R, Berencsi K, Caputo L, Gimotty P, et al. (2006) Migration of cytotoxic T lymphocytes toward melanoma cells in three-dimensional organotypic culture is dependent on CCL2 and CCR4. European journal of immunology 36: 457–467.
[27]  Chiu YC, Fong YC, Lai CH, Hung CH, Hsu HC, et al. (2008) Thrombin-induced IL-6 production in human synovial fibroblasts is mediated by PAR1, phospholipase C, protein kinase C alpha, c-Src, NF-kappa B and p300 pathway. Mol Immunol 45: 1587–1599.
[28]  Hsieh HL, Sun CC, Wang TS, Yang CM (2008) PKC-delta/c-Src-mediated EGF receptor transactivation regulates thrombin-induced COX-2 expression and PGE(2) production in rat vascular smooth muscle cells. Biochimica et biophysica acta 1783: 1563–1575.
[29]  Basu A, Adkins B, Basu C (2008) Down-regulation of caspase-2 by rottlerin via protein kinase C-delta-independent pathway. Cancer Res 68: 2795–2802.
[30]  Lin WN, Luo SF, Lin CC, Hsiao LD, Yang CM (2009) Differential involvement of PKC-dependent MAPKs activation in lipopolysaccharide-induced AP-1 expression in human tracheal smooth muscle cells. Cellular signalling 21: 1385–1395.
[31]  Cai K, Qi D, Hou X, Wang O, Chen J, et al. (2011) MCP-1 upregulates amylin expression in murine pancreatic beta cells through ERK/JNK-AP1 and NF-kappaB related signaling pathways independent of CCR2. PloS one 6: e19559.
[32]  Tang CH, Tsai CC (2012) CCL2 increases MMP-9 expression and cell motility in human chondrosarcoma cells via the Ras/Raf/MEK/ERK/NF-kappaB signaling pathway. Biochemical pharmacology 83: 335–344.
[33]  Zhou J, Wang KC, Wu W, Subramaniam S, Shyy JY, et al. (2011) MicroRNA-21 targets peroxisome proliferators-activated receptor-alpha in an autoregulatory loop to modulate flow-induced endothelial inflammation. Proceedings of the National Academy of Sciences of the United States of America 108: 10355–10360.
[34]  Madry H, Luyten FP, Facchini A (2012) Biological aspects of early osteoarthritis. Knee surgery, sports traumatology, arthroscopy : official journal of the ESSKA 20: 407–422.
[35]  Hamanishi C, Hashima M, Satsuma H, Tanaka S (1996) Protein kinase C activator inhibits progression of osteoarthritis induced in rabbit knee joints. The Journal of laboratory and clinical medicine 127: 540–544.
[36]  Leitges M, Elis W, Gimborn K, Huber M (2001) Rottlerin-independent attenuation of pervanadate-induced tyrosine phosphorylation events by protein kinase C-delta in hemopoietic cells. Lab Invest 81: 1087–1095.
[37]  Luo SF, Fang RY, Hsieh HL, Chi PL, Lin CC, et al. (2010) Involvement of MAPKs and NF-kappaB in tumor necrosis factor alpha-induced vascular cell adhesion molecule 1 expression in human rheumatoid arthritis synovial fibroblasts. Arthritis and rheumatism 62: 105–116.
[38]  Ahmad M, Theofanidis P, Medford RM (1998) Role of activating protein-1 in the regulation of the vascular cell adhesion molecule-1 gene expression by tumor necrosis factor-alpha. The Journal of biological chemistry 273: 4616–4621.
[39]  Lazzerini G, Del Turco S, Basta G, O'Loghlen A, Zampolli A, et al. (2009) Prominent role of NF-kappaB in the induction of endothelial activation by endogenous nitric oxide inhibition. Nitric oxide : biology and chemistry/official journal of the Nitric Oxide Society 21: 184–191.
[40]  Wagner EF (2010) Bone development and inflammatory disease is regulated by AP-1 (Fos/Jun). Annals of the rheumatic diseases 69 Suppl 1i86–88.


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