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in Combination with Either IL-4 or IL-13 through Increased mRNA Stability
From the Department of Pharmacology,*
University College
London, and the Novartis Institute for Medical
Sciences,
London, United Kingdom
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
4ß1 and 4ß7. Elevated levels of VCAM-1 expression are thought
to be a consequence of the presence of inflammatory mediators,
in particular IL-1ß and TNF-. Fibroblast-like synoviocytes rapidly
up-regulate VCAM-1 expression in response to IL-1ß and
TNF-, but also to IL-4. However, we now show that
the response to IL-1ß or TNF- 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-, 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.
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