Sustained elevated levels of VCAM-1 in cultured fibroblast-like synoviocytes can be achieved by TNF-alpha in combination with either IL-4 or IL-13 through increased mRNA stability.
Rheumatoid arthritis is characterized by hyperplasia of the synovial lining and invasion of cartilage and bone by a subset of resident synovial cells named fibroblast-like synoviocytes. They are characterized by elevated expression of the vascular cell adhesion molecule-1 (VCAM-1). The intensity of VCAM-1 expression correlates with the degree of inflammation of the synovial joint. Differential VCAM-1 expression may determine inflammatory cell accumulation through its interaction with leukocytes that express the counterreceptor integrins alpha4beta1 and alpha4beta7. Elevated levels of VCAM-1 expression are thought to be a consequence of the presence of inflammatory mediators, in particular IL-1beta and TNF-alpha. Fibroblast-like synoviocytes rapidly up-regulate VCAM-1 expression in response to IL-1beta and TNF-alpha, but also to IL-4. However, we now show that the response to IL-1beta or TNF-alpha is of a brief transient nature, even when applied continuously over a period of 12 days, whereas the response to IL-4 or IL-13 is sustained. Great synergy is obtained by combining either IL-4 or IL-13 with TNF-alpha, which results in a highly elevated but also sustained expression of VCAM-1. The mechanism by which IL-4 or IL-13 prolongs VCAM-1 expression can be explained by a dramatic increase in the half-life of VCAM-1 mRNA.
Croft
D
D
Department of Pharmacology, University College London, London, United Kingdom.
McIntyre
P
P
Wibulswas
A
A
Kramer
I
I
D001172:Arthritis, Rheumatoid / Q000378:metabolism; D002478:Cells, Cultured; D004357:Drug Synergism; D005434:Flow Cytometry; D006801:Humans; D007150:Immunohistochemistry; D007375:Interleukin-1 / Q000494:pharmacology; D018793:Interleukin-13 / Q000494:pharmacology*; D015847:Interleukin-4 / Q000494:pharmacology*; D012323:RNA Processing, Post-Transcriptional / Q000187:drug effects; D012333:RNA, Messenger / Q000187:drug effects* / Q000378:metabolism; D013583:Synovial Membrane / Q000378:metabolism*; D013997:Time Factors; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*; D019010:Vascular Cell Adhesion Molecule-1 / Q000378:metabolism*
D007375:Interleukin-1; D018793:Interleukin-13; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; D019010:Vascular Cell Adhesion Molecule-1; D015847:Interleukin-4