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*
Division of Rheumatology, University of Connecticut Health Center, Farmington, CT 06030; and
Research Service, Veterans Administration Connecticut Healthcare System, Newington, CT 06111
It has long been recognized that in most inflamed arthritic joints
the coagulation system is activated, leading to the local generation of
fibrin, and it has long been hypothesized that the local fibrin
deposition promotes inflammation and tissue destruction. However, only
recently has the direct effect of fibrin on the inflammatory process
been seriously investigated, and specific roles assigned to fibrin or
its products as mediators of the inflammatory process. Although fibrin
and/or fibrinogen (fibrin(ogen)) is abundantly present in inflamed
tissues and joints rich in fibroblastic cells, no significant data on
fibrin(ogen)-induced gene expression by fibroblasts have been
published. We now demonstrate that coculture of human synovial
fibroblasts with fibrin(ogen) results in the up-regulation of ICAM-1 as
well as increased production of the chemokines IL-8 and growth-related
oncogene-
. Increased ICAM-1 expression was fibrin(ogen)
dose-dependent and was demonstrated by ELISA, flow cytometry, and
functional adhesion assays. Levels of ICAM-1 induced by fibrin(ogen)
were comparable to those that could be induced by cytokine stimulation.
Fibrin(ogen) stimulation of ICAM-1 could be suppressed by
pyrrolidinedithiocarbamate, an inhibitor of NF-
B activation.
Chemokine production was induced by fibrin(ogen) in cell culture
supernatants >100-fold as compared with controls. Thus, through its
activation of synovial fibroblasts, fibrin(ogen) deposition may promote
the recruitment (via chemokines) and retention (via adhesion molecules)
of lymphocytes within the arthritic joint.
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