Up‐regulation by tumor necrosis factor α of intercellular adhesion molecule 1 expression and function in synovial fibroblasts and its inhibition by glucocorticoids

Abstract

Abstract Objective. To examine the regulation of the intercellular adhesion molecule 1 (ICAM‐1) gene in cultured human synovial fibroblasts in response to tumor necrosis factor α (TNFα), and investigate its modulation by the synthetic glucocorticoid, dexamethasone. Methods. Cell surface expression of ICAM‐1 was determined by flow cytometry, enzyme immunoassay, and immunoprecipitation. ICAM‐1 messenger RNA (mRNA) levels were monitored by Northern blot. ICAM‐1 function was determined by measuring the adhesion of monocytes to synovial fibroblasts. Results. ICAM‐1 expression on unstimulated cells was weak but was rapidly enhanced in both a time‐ and dose‐dependent manner following exposure to TNFα. Treatment of the cells with TNFα also resulted in both a time‐ and dose‐dependent increase in steady‐state ICAM‐1 mRNA levels, as determined by Northern blot. The increased expression of ICAM‐1 was inhibited by cycloheximide and actinomycin D. Cultured synovial fibroblasts from patients with rheumatoid and nonrheumatoid arthropathies responded similarly to TNFα. Adhesion studies demonstrated that ICAM‐1 is involved in the adherence of peripheral blood monocytes to TNFα‐activated synovial fibroblasts. In addition, dexamethasone inhibited TNFα‐induced surface expression of ICAM‐1, accumulation of ICAM‐1 mRNA, and adhesion of monocytes to TNFα‐activated synovial fibroblasts. Conclusion. These combined results provide further evidence of an important role of ICAM‐1 in inflammatory synovitis, as well as a potentially novel site of antiinflammatory action of glucocorticoids.