IL-6 and matrix metalloproteinase-1 are regulated by the cyclin-dependent kinase inhibitor p21 in synovial fibroblasts.
During the pathogenesis of rheumatoid arthritis (RA), the synovial fibroblasts increase in number and produce proinflammatory cytokines and matrix metalloproteinases (MMPs) that function to promote inflammation and joint destruction. Recent investigations have suggested that cell cycle activity and inflammation may be linked. However, little is known about the mechanisms responsible for the coordinate regulation of proliferation and the expression of proinflammatory molecules in RA synovial fibroblasts. Here, we demonstrate a 50 +/- 10% decrease in the expression of p21, a cell cycle inhibitor, in the synovial fibroblast population from RA compared with osteoarthritis (OA) synovial tissue. Moreover, p21 positivity in the synovial fibroblasts inversely correlates with medium synovial lining thickness (r = -0.76; p < 0.02). The expression of p21 is also reduced in isolated RA synovial fibroblasts compared with OA synovial fibroblasts. Adenovirus-mediated delivery of p21 (Ad-p21) arrests both RA and OA synovial fibroblasts in the G(0)/G(1) phase of the cell cycle without inducing cytotoxicity. However, the spontaneous production of IL-6 and MMP-1 is suppressed only in the Ad-p21-infected RA synovial fibroblasts, indicating a novel role for p21 in RA. Analyses of p21-deficient mouse synovial fibroblasts reveal a 100-fold increase in IL-6 protein and enhance IL-6 and MMP-3 mRNA. Restoration of p21, but not overexpression of Rb, which also induces G(0)/G(1) cell cycle arrest, decreases IL-6 synthesis in p21-null synovial fibroblasts. Furthermore, in RA synovial fibroblasts the ectopic expression of p21 reduces activation of the AP-1 transcription factor. Additionally, p21-null synovial fibroblasts display enhanced activation of AP-1 compared with wild-type synovial fibroblasts. These data suggest that alterations in p21 expression may activate AP-1 leading to enhanced proinflammatory cytokine and MMP production and development of autoimmune disease.
Perlman
Harris
H
Division of Rheumatology, Northwestern University, Feinberg School of Medicine, Chicago, IL 60611, USA. perlmanh@slu.edu
Bradley
Kathleen
K
Liu
Hongtao
H
Cole
Shawn
S
Shamiyeh
Eli
E
Smith
Roy C
RC
Walsh
Kenneth
K
Fiore
Stefano
S
Koch
Alisa E
AE
Firestein
Gary S
GS
Haines
G Kenneth
GK
Pope
Richard M
RM
D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D001172:Arthritis, Rheumatoid / Q000201:enzymology / Q000378:metabolism / Q000473:pathology; D002453:Cell Cycle / Q000235:genetics; D002478:Cells, Cultured; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins / Q000096:biosynthesis / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D015536:Down-Regulation / Q000235:genetics; D005347:Fibroblasts / Q000201:enzymology* / Q000276:immunology* / Q000378:metabolism; D005822:Genetic Vectors / Q000494:pharmacology; D006131:Growth Inhibitors / Q000235:genetics / Q000494:pharmacology; D006801:Humans; D015850:Interleukin-6 / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D020781:Matrix Metalloproteinase 1 / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D019278:Matrix Metalloproteinase 3 / Q000096:biosynthesis / Q000378:metabolism; D061965:Matrix Metalloproteinase Inhibitors; D051379:Mice; D018345:Mice, Knockout; D012333:RNA, Messenger / Q000037:antagonists & inhibitors; D016160:Retinoblastoma Protein / Q000096:biosynthesis / Q000235:genetics; D013583:Synovial Membrane / Q000201:enzymology* / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D018808:Transcription Factor AP-1 / Q000037:antagonists & inhibitors / Q000378:metabolism; D000093242:Interleukin-6 Inhibitors
D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; D006131:Growth Inhibitors; D015850:Interleukin-6; D020781:Matrix Metalloproteinase 1; D019278:Matrix Metalloproteinase 3; D061965:Matrix Metalloproteinase Inhibitors; D012333:RNA, Messenger; D016160:Retinoblastoma Protein; D018808:Transcription Factor AP-1; D000093242:Interleukin-6 Inhibitors; C493956:CDKN1A protein, human; C493957:Cdkn1a protein, mouse