Up-regulation by tumor necrosis factor alpha of intercellular adhesion molecule 1 expression and function in synovial fibroblasts and its inhibition by glucocorticoids.
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 alpha (TNF alpha), 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 TNF alpha. Treatment of the cells with TNF alpha 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 TNF alpha. Adhesion studies demonstrated that ICAM-1 is involved in the adherence of peripheral blood monocytes to TNF alpha-activated synovial fibroblasts. In addition, dexamethasone inhibited TNF alpha-induced surface expression of ICAM-1, accumulation of ICAM-1 mRNA, and adhesion of monocytes to TNF alpha-activated synovial fibroblasts.


CONCLUSIONS
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.
Tessier
P
P
Inflammation, Immunology, and Rheumatology Research Unit, Laval University Medical Center, Sainte-Foy, Quebec, Canada.
Audette
M
M
Cattaruzzi
P
P
McColl
S R
SR
D002448:Cell Adhesion / Q000187:drug effects; D015815:Cell Adhesion Molecules / Q000096:biosynthesis / Q000235:genetics* / Q000502:physiology*; D003907:Dexamethasone / Q000494:pharmacology; D005347:Fibroblasts / Q000737:chemistry / Q000166:cytology / Q000502:physiology*; D015870:Gene Expression / Q000187:drug effects; D006801:Humans; D018799:Intercellular Adhesion Molecule-1; D009000:Monocytes / Q000166:cytology; D014176:Protein Biosynthesis; D013583:Synovial Membrane / Q000166:cytology*; D014158:Transcription, Genetic; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*; D015854:Up-Regulation / Q000187:drug effects
D015815:Cell Adhesion Molecules; D014409:Tumor Necrosis Factor-alpha; D018799:Intercellular Adhesion Molecule-1; D003907:Dexamethasone