Chemerin induces CCL2 and TLR4 in synovial fibroblasts of patients with rheumatoid arthritis and osteoarthritis.
BACKGROUND
Chemerin stimulates migration of leukocytes to sites of inflammation and also increases inflammatory signaling in chondrocytes suggesting a function of chemerin in joint inflammation. Synovial fibroblasts (SF) are critically involved in synovitis and subsequent cartilage destruction. Here, we analyzed whether synovial fibroblasts express chemerin and its receptor CMKLR1. Further, the role of chemerin in synovial fibroblast chemotaxis, proliferation, insulin response and release of inflammatory proteins was studied.


METHODS
Synovial tissue sections were labeled with chemerin antibody and chemerin was measured in synovial fluid by ELISA. Chemerin mRNA and protein as well as CMKLR1 expression were determined in SFs from patients with osteoarthritis (OA) and rheumatoid arthritis (RA). Effects of chemerin on cytokines, chemokines and matrix metalloproteinases (MMP), and on proliferation, migration and insulin signaling were analyzed appropriately.


RESULTS
SFs expressed CMKLR1 and chemerin mRNA, and chemerin protein was found in cell supernatants of synovial fibroblasts. Immunohistochemistry detected chemerin in synovial tissue predominantly localized within the lining layer. Chemerin was present in synovial fluids of RA, OA and psoriatic arthritis patients in similar concentrations. Chemerin neither increased IL-6 levels nor MMP-2 or -9 activity in SFs. Also, it did not act as a chemoattractant for these cells. With respect to intracellular signaling, neither basal nor insulin-mediated phosphorylation of Akt was affected. However, chemerin significantly increased TLR4 mRNA and synthesis of CCL2 in SFs while CCL4 and -5 were not altered. Cell proliferation of SFs, however, was modestly reduced by chemerin.


CONCLUSIONS
These data show that human SFs express both chemerin and its receptor. As chemerin enhanced expression of TLR4 and induced release of CCL2 in SFs, a role of this protein in innate immune system-associated joint inflammation is proposed.
Department of Internal Medicine I, Regensburg University Hospital, D-93042 Regensburg, Germany.
Kristina
K
Eisinger
Sabrina
S
Bauer
Andreas
A
Schäffler
Roland
R
Walter
Elena
E
Neumann
Christa
C
Buechler
Ulf
U
Müller-Ladner
Klaus W
KW
Frommer
D000906:Antibodies; D001172:Arthritis, Rheumatoid / Q000276:immunology / Q000503:physiopathology*; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D018932:Chemokine CCL2 / Q000235:genetics / Q000378:metabolism*; D018925:Chemokines / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology*; D005347:Fibroblasts / Q000276:immunology / Q000378:metabolism*; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins; D008297:Male; D010003:Osteoarthritis / Q000276:immunology / Q000503:physiopathology*; D012333:RNA, Messenger / Q000235:genetics; D019707:Receptors, Chemokine / Q000235:genetics / Q000378:metabolism; D013582:Synovial Fluid / Q000166:cytology / Q000378:metabolism; D013583:Synovial Membrane / Q000166:cytology / Q000378:metabolism; D051197:Toll-Like Receptor 4 / Q000235:genetics / Q000378:metabolism*; D015854:Up-Regulation / Q000187:drug effects
D000906:Antibodies; C111835:CCL2 protein, human; C102741:CMKLR1 protein, human; D018932:Chemokine CCL2; D018925:Chemokines; D036341:Intercellular Signaling Peptides and Proteins; C478630:RARRES2 protein, human; D012333:RNA, Messenger; D019707:Receptors, Chemokine; C495345:TLR4 protein, human; D051197:Toll-Like Receptor 4