TY - JOUR
T1 - Exuberant expression of chemokine genes by adult human articular chondrocytes in response to IL-1β
AU - Sandell, L. J.
AU - Xing, X.
AU - Franz, C.
AU - Davies, S.
AU - Chang, L. W.
AU - Patra, D.
N1 - Funding Information:
The authors would like to thank Drs Douglas McDonald and Joseph Borrelli for normal cartilage and Drs John Clohisy, and Robert Barrack and Head Nurse, Keith Foreman, for cartilage from patients with osteoarthritis. The authors would also like to thank the Genome Sequencing Center at the Washington University School of Medicine for their assistance with the microarray analysis. These studies were funded by The National Institute for Arthritis, Musculoskeletal and Skin Diseases (R01 AR05084, R01 AR045550 and R01 AR036994).
PY - 2008/12
Y1 - 2008/12
N2 - Objective: To provide a more complete picture of the effect of interleukin-1 beta (IL-1β) on adult human articular chondrocyte gene expression, in contrast to the candidate gene approach. Design: Chondrocytes from human knee cartilage were cultured in medium containing IL-1β. Changes in gene expression were analyzed by microarray and reverse transcriptase-polymerase chain reaction analysis. The ability of transforming growth factor beta-1 (TGF-β1), fibroblast growth factor (FGF)-18, and bone morphogenetic protein 2 (BMP-2) to alter the effects of IL-1β was analyzed. Computational analysis of the promoter regions of differentially expressed genes for transcription factor binding motifs was performed. Results: IL-1β-treated human chondrocytes showed significant increases in the expression of granulocyte colony stimulating factor-3, endothelial leukocyte adhesion molecule 1 and leukemia inhibitory factor as well as for a large group of chemokines that include CXCL1, CXCL2, CXCL3, CXCL5, CXCL6, CXCL8, CCL2, CCL3, CCL4, CCL5, CCL8, CCL20, CCL3L1, CX3CL1 and the cytokine IL-6. As expected, the mRNA for matrix metalloproteinase (MMP)-13 and BMP-2 also increased while mRNA for the matrix genes COL2A1 and aggrecan was down-regulated. A subset of chemokines increased rapidly at very low levels of IL-1β. The phenotype induced by IL-1β was partially reversed by TGF-β1, but not by BMP-2. In the presence of IL-1β, FGF-18 increased expression of ADAMTS-4, aggrecan, BMP-2, COL2A1, CCL3, CCL4, CCL20, CXCL1, CXCL3, CXCL6, IL-1β, IL-6, and IL-8 and decreased ADAMTS-5, MMP-13, CCL2, and CCL8. Computational analysis revealed a high likelihood that the most up-regulated chemokines are regulated by the transcription factors myocyte enhancer binding factor-3 (MEF-3), CCAAT/enhancer binding protein (C/EBP) and nuclear factor-kappa B (NF-κB). Conclusion: IL-1β has a diverse effect on gene expression profile in human chondrocytes affecting matrix genes as well as chemokines and cytokines. TGF-β1 has the ability to antagonize some of the phenotype induced by IL-1β.
AB - Objective: To provide a more complete picture of the effect of interleukin-1 beta (IL-1β) on adult human articular chondrocyte gene expression, in contrast to the candidate gene approach. Design: Chondrocytes from human knee cartilage were cultured in medium containing IL-1β. Changes in gene expression were analyzed by microarray and reverse transcriptase-polymerase chain reaction analysis. The ability of transforming growth factor beta-1 (TGF-β1), fibroblast growth factor (FGF)-18, and bone morphogenetic protein 2 (BMP-2) to alter the effects of IL-1β was analyzed. Computational analysis of the promoter regions of differentially expressed genes for transcription factor binding motifs was performed. Results: IL-1β-treated human chondrocytes showed significant increases in the expression of granulocyte colony stimulating factor-3, endothelial leukocyte adhesion molecule 1 and leukemia inhibitory factor as well as for a large group of chemokines that include CXCL1, CXCL2, CXCL3, CXCL5, CXCL6, CXCL8, CCL2, CCL3, CCL4, CCL5, CCL8, CCL20, CCL3L1, CX3CL1 and the cytokine IL-6. As expected, the mRNA for matrix metalloproteinase (MMP)-13 and BMP-2 also increased while mRNA for the matrix genes COL2A1 and aggrecan was down-regulated. A subset of chemokines increased rapidly at very low levels of IL-1β. The phenotype induced by IL-1β was partially reversed by TGF-β1, but not by BMP-2. In the presence of IL-1β, FGF-18 increased expression of ADAMTS-4, aggrecan, BMP-2, COL2A1, CCL3, CCL4, CCL20, CXCL1, CXCL3, CXCL6, IL-1β, IL-6, and IL-8 and decreased ADAMTS-5, MMP-13, CCL2, and CCL8. Computational analysis revealed a high likelihood that the most up-regulated chemokines are regulated by the transcription factors myocyte enhancer binding factor-3 (MEF-3), CCAAT/enhancer binding protein (C/EBP) and nuclear factor-kappa B (NF-κB). Conclusion: IL-1β has a diverse effect on gene expression profile in human chondrocytes affecting matrix genes as well as chemokines and cytokines. TGF-β1 has the ability to antagonize some of the phenotype induced by IL-1β.
KW - Binding motifs
KW - Chemokines
KW - Chondrocytes
KW - IL-1β
KW - TGF-β1
KW - Transcription factor
UR - http://www.scopus.com/inward/record.url?scp=55349088908&partnerID=8YFLogxK
U2 - 10.1016/j.joca.2008.04.027
DO - 10.1016/j.joca.2008.04.027
M3 - Article
C2 - 18565769
AN - SCOPUS:55349088908
SN - 1063-4584
VL - 16
SP - 1560
EP - 1571
JO - Osteoarthritis and Cartilage
JF - Osteoarthritis and Cartilage
IS - 12
ER -