Expression of interleukin-22 in rheumatoid arthritis: potential role as a proinflammatory cytokine.
OBJECTIVE
Interleukin-22 (IL-22) is a novel cytokine of the IL-10 family. Although its pathophysiologic function is largely unknown, induction of acute-phase responses by IL-22 has suggested proinflammatory properties. In this study, we sought to examine whether IL-22 plays a role in the pathogenesis of rheumatoid arthritis (RA).


METHODS
Expression of IL-22 and IL-22 receptor 1 (IL-22R1) was examined by reverse transcription-polymerase chain reaction (RT-PCR), Western blot, and immunohistochemical analysis. The effects of recombinant IL-22 (rIL-22) on cultured synovial fibroblasts derived from RA patients (RASF), with regard to the proliferation of synovial fibroblasts and production of monocyte chemoattractant protein 1 (MCP-1), were examined by alamer blue assay and enzyme-linked immunosorbent assay, respectively.


RESULTS
IL-22 messenger RNA was detected by RT-PCR in RA synovial tissues and mononuclear cells isolated from RA synovial fluid samples. High levels of IL-22 were expressed both in the lining and the sublining layers of RA synovial tissues. Staining for vimentin and CD68, as markers of synovial fibroblasts and macrophages, respectively, showed that the majority of IL-22-positive cells were synovial fibroblasts and macrophages. IL-22R1 was also expressed in both the lining and the sublining layers of RA synovial tissues. The majority of cells expressing IL-22R1 were positive for vimentin, but not for CD68. Expression of IL-22 and IL-22R1 in RASF was confirmed by RT-PCR and Western blot analysis. In vitro, rIL-22 significantly increased proliferation of RASF and production of MCP-1 by RASF above the value of medium controls. Moreover, MAPK activation was induced in RASF in response to IL-22 stimulation.


CONCLUSIONS
These data suggest that IL-22, produced by synovial fibroblasts and macrophages, promotes inflammatory responses in RA synovial tissues by inducing the proliferation and chemokine production of synovial fibroblasts.
Ikeuchi
Hidekazu
H
Gunma University Graduate School of Medicine, Maebashi, Japan.
Kuroiwa
Takashi
T
Hiramatsu
Noriyuki
N
Kaneko
Yoriaki
Y
Hiromura
Keiju
K
Ueki
Kazue
K
Nojima
Yoshihisa
Y
D000818:Animals; D015703:Antigens, CD / Q000378:metabolism; D015214:Antigens, Differentiation, Myelomonocytic / Q000378:metabolism; D001172:Arthritis, Rheumatoid / Q000378:metabolism* / Q000473:pathology; D015415:Biomarkers / Q000378:metabolism; D015153:Blotting, Western; D049109:Cell Proliferation; D002478:Cells, Cultured; D018932:Chemokine CCL2 / Q000096:biosynthesis / Q000235:genetics; D004789:Enzyme Activation; D006801:Humans; D007124:Immunoenzyme Techniques; D007378:Interleukins / Q000096:biosynthesis* / Q000235:genetics / Q000494:pharmacology; D007963:Leukocytes, Mononuclear / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D012333:RNA, Messenger / Q000378:metabolism; D018123:Receptors, Interleukin / Q000096:biosynthesis* / Q000235:genetics; D011994:Recombinant Proteins / Q000494:pharmacology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013582:Synovial Fluid / Q000166:cytology / Q000378:metabolism; D013583:Synovial Membrane / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D014746:Vimentin / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism; D000097043:Interleukin-22; D000097382:CD68 Molecule
D015703:Antigens, CD; D015214:Antigens, Differentiation, Myelomonocytic; D015415:Biomarkers; D018932:Chemokine CCL2; D007378:Interleukins; D012333:RNA, Messenger; D018123:Receptors, Interleukin; D011994:Recombinant Proteins; D014746:Vimentin; D048051:p38 Mitogen-Activated Protein Kinases; D000097043:Interleukin-22; C111835:CCL2 protein, human; C067980:CD68 antigen, human; D000097382:CD68 Molecule; C415369:interleukin-22 receptor