Acute-phase serum amyloid A stimulation of angiogenesis, leukocyte recruitment, and matrix degradation in rheumatoid arthritis through an NF-kappaB-dependent signal transduction pathway.
OBJECTIVE
To examine the role of the acute-phase protein serum amyloid A (A-SAA) in regulating cell adhesion molecule expression, leukocyte recruitment, and angiogenesis in rheumatoid arthritis (RA).


METHODS
Intercellular adhesion molecule 1 (ICAM-1), vascular cell adhesion molecule 1 (VCAM-1), and matrix metalloproteinase 1 (MMP-1) expression was examined in RA fibroblast-like synoviocytes (FLS) and human microvascular endothelial cells (HMVECs) using flow cytometry and enzyme-linked immunosorbent assay techniques. Peripheral blood mononuclear cell (PBMC) adhesion to FLS/HMVECs was determined by flow cytometry. Angiogenesis was examined using a Boyden chemotaxis chamber and Matrigel tubule formation. NF-kappaB/IkappaBalpha mediation of the effects of A-SAA was investigated using a specific NF-kappaB inhibitor and Western blotting.


RESULTS
A-SAA significantly enhanced the time- and dose-dependent expression of ICAM-1 and VCAM-1 as effectively as interleukin-1beta/tumor necrosis factor alpha. A-SAA promoted the adhesion of PBMCs to FLS and HMVECs. In addition, A-SAA at 10 mug/ml and 50 mug/ml significantly increased endothelial cell tube formation by 69% and 207%, respectively. At 50 mug/ml and 100 mug/ml, A-SAA increased HMVEC migration by 188 +/- 54% and 296 +/- 71%, respectively (mean +/- SEM). A-SAA-induced expression of VCAM-1, ICAM-1, and MMP-1 was down-regulated by NF-kappaB inhibition. Furthermore, A-SAA induced IkappaBalpha degradation and NF-kappaB translocation, suggesting that its proinflammatory effects are mediated in part by NF-kappaB signaling.


CONCLUSIONS
Our findings demonstrate the ability of A-SAA to induce adhesion molecule expression, angiogenesis, and matrix degradation, mechanisms that are mediated by NF-kappaB. Targeting A-SAA and its signaling pathways may represent a new therapeutic approach in the treatment of RA.
Mullan
Ronan H
RH
Dept. of Rheumatology, Education and Research Centre, St. Vincent's University Hospital, Elm Park, Dublin 4, Ireland.
Bresnihan
Barry
B
Golden-Mason
Lucy
L
Markham
Trevor
T
O'Hara
Rosemary
R
FitzGerald
Oliver
O
Veale
Douglas J
DJ
Fearon
Ursula
U
D001172:Arthritis, Rheumatoid / Q000276:immunology*; D002478:Cells, Cultured; D002634:Chemotaxis, Leukocyte; D005109:Extracellular Matrix / Q000378:metabolism; D006801:Humans; D018799:Intercellular Adhesion Molecule-1 / Q000502:physiology; D016328:NF-kappa B / Q000502:physiology*; D009389:Neovascularization, Pathologic / Q000209:etiology*; D000685:Serum Amyloid A Protein / Q000502:physiology*; D015398:Signal Transduction; D013583:Synovial Membrane / Q000098:blood supply*; D019010:Vascular Cell Adhesion Molecule-1 / Q000502:physiology
D016328:NF-kappa B; D000685:Serum Amyloid A Protein; D019010:Vascular Cell Adhesion Molecule-1; D018799:Intercellular Adhesion Molecule-1