Chemokines regulate IL-6 and IL-8 production by fibroblast-like synoviocytes from patients with rheumatoid arthritis.
Rheumatoid arthritis (RA) is characterized by proliferation of synoviocytes that produce inflammatory cytokines and chemokines. The expressed chemokines are thought to be involved in the migration of inflammatory cells into the synovium. In this study we show that CCL2/monocyte chemotactic protein-1, CCL5/RANTES, and CXCL12/stromal cell-derived factor-1 enhanced IL-6 and IL-8 production by fibroblast-like synoviocytes (FLS) from patients with RA, and their corresponding receptors, CCR2, CCR5, and CXCR4, respectively, were expressed by RA FLS. The chemokines stimulated RA FLS more effectively than skin fibroblasts. Culture with CCL2 enhanced phosphorylation of extracellular signal-related kinase 1 (ERK1) and ERK2, but not phosphorylation of p38 or Src. Moreover, activation of ERK1/2 was inhibited by pertussis toxin, a G(i)-coupled protein inhibitor, and RS-504393, CCR2 antagonist, suggesting that ERK1/2 was activated by CCL2 via CCR2 and G(i)-coupled protein. On the other hand, CCL2, CCL5, and CXCL12 were expressed on RA FLS, and their production was regulated by TNF-alpha, IL-1beta, and TGF-beta1. Our results indicate that the chemokines not only play a role in inflammatory cell migration, but are also involved in the activation of FLS in RA synovium, possibly in an autocrine or paracrine manner.
Nanki
T
T
Department of Bioregulatory Medicine and Rheumatology, Tokyo Medical and Dental University Graduate School, Tokyo, Japan. nanki.rheu@tmd.ac.jp
Nagasaka
K
K
Hayashida
K
K
Saita
Y
Y
Miyasaka
N
N
D001172:Arthritis, Rheumatoid / Q000276:immunology*; D018932:Chemokine CCL2 / Q000502:physiology*; D018946:Chemokine CCL5 / Q000502:physiology*; D054377:Chemokine CXCL12; D019743:Chemokines, CXC / Q000502:physiology*; D004789:Enzyme Activation; D005347:Fibroblasts / Q000378:metabolism; D006801:Humans; D015850:Interleukin-6 / Q000096:biosynthesis*; D016209:Interleukin-8 / Q000096:biosynthesis*; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D019707:Receptors, Chemokine / Q000032:analysis / Q000096:biosynthesis; D013583:Synovial Membrane / Q000166:cytology / Q000378:metabolism*
C515255:CXCL12 protein, human; D018932:Chemokine CCL2; D018946:Chemokine CCL5; D054377:Chemokine CXCL12; D019743:Chemokines, CXC; D015850:Interleukin-6; D016209:Interleukin-8; D019707:Receptors, Chemokine; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases