Expression of interleukin-21 receptor, but not interleukin-21, in synovial fibroblasts and synovial macrophages of patients with rheumatoid arthritis.
OBJECTIVE
To determine the role and expression of the cytokine/receptor pair interleukin-21 (IL-21)/IL-21 receptor (IL-21R) in rheumatoid arthritis (RA).


METHODS
The expression of IL-21R and IL-21 was analyzed by TaqMan real-time polymerase chain reaction (PCR) and in situ hybridization of synovial biopsy samples from patients with RA and osteoarthritis (OA). Double labeling by immunohistochemistry after in situ hybridization was performed with anti-CD68 antibodies. The expression of IL-21R at the protein level was confirmed by Western blotting. Stimulation experiments were performed with recombinant IL-1beta, tumor necrosis factor alpha (TNFalpha), platelet-derived growth factor (PDGF), and transforming growth factor beta (TGFbeta). The role of IL-21R in cartilage destruction was analyzed in the SCID mouse coimplantation model of RA.


RESULTS
IL-21R was found in total RNA extracts and in synovial biopsy samples from RA patients, whereas no expression or only minimal expression was seen in samples from OA patients. Double labeling indicated that both synovial macrophages and synovial fibroblasts expressed IL-21R. Western blotting with anti-IL-21R antibodies confirmed the expression of IL-21R protein in RA synovial fibroblasts (RASFs). Of note, IL-21 was not detectable by real-time PCR and in situ hybridization in the same samples in vivo as in vitro. The level of expression of IL-21R messenger RNA (mRNA) was not altered by stimulation with IL-1beta, TNFalpha, PDGF, or TGFbeta. Interestingly, in the SCID mouse coimplantation model, RASFs did not maintain their expression of IL-21R at sites of invasion into the cartilage. Similarly, IL-21R mRNA was not expressed at sites of invasion into cartilage and bone in RA synovium.


CONCLUSIONS
Our data demonstrate that IL-21R is expressed in RA synovium by RASFs and synovial macrophages. IL-21R is associated with the activated phenotype of RASFs independently of the major proinflammatory cytokines IL-1beta and TNFalpha, but correlates negatively with the destruction of articular cartilage and bone.
Jüngel
Astrid
A
Center of Experimental Rheumatology, Department of Rheumatology, University Hospital Zurich, Gloriastrasse 25, CH-8091 Zurich, Switzerland.
Distler
Jörg H W
JH
Kurowska-Stolarska
Mariola
M
Seemayer
Christian A
CA
Seibl
Reinhart
R
Forster
Adrian
A
Michel
Beat A
BA
Gay
Renate E
RE
Emmrich
Frank
F
Gay
Steffen
S
Distler
Oliver
O
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D001172:Arthritis, Rheumatoid / Q000276:immunology* / Q000473:pathology / Q000503:physiopathology*; D002356:Cartilage / Q000473:pathology; D002478:Cells, Cultured; D005347:Fibroblasts / Q000166:cytology / Q000502:physiology; D015870:Gene Expression / Q000187:drug effects / Q000276:immunology; D006801:Humans; D007375:Interleukin-1 / Q000494:pharmacology; D053738:Interleukin-21 Receptor alpha Subunit; D007378:Interleukins / Q000235:genetics* / Q000378:metabolism; D008264:Macrophages / Q000166:cytology / Q000276:immunology; D051379:Mice; D016513:Mice, SCID; D018123:Receptors, Interleukin / Q000235:genetics*; D053655:Receptors, Interleukin-21; D013582:Synovial Fluid / Q000378:metabolism; D013583:Synovial Membrane / Q000276:immunology / Q000473:pathology; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D000098546:Interleukin-21
D000970:Antineoplastic Agents; C508117:IL21R protein, human; C508118:Il21r protein, mouse; D007375:Interleukin-1; D053738:Interleukin-21 Receptor alpha Subunit; D007378:Interleukins; D018123:Receptors, Interleukin; D053655:Receptors, Interleukin-21; D014409:Tumor Necrosis Factor-alpha; D000098546:Interleukin-21