Induction of MMP-13 expression by soluble human glucocorticoid-induced tumor necrosis factor receptor in fibroblast-like synovial cells 1

SummaryObjectiveWe tested the hypothesis that human glucocorticoid-induced tumor necrosis factor receptor (hGITR/TR11) expressed on the surface of activated CD4+ T cells is responsible for up-regulating the production of matrix metalloproteinase (MMP)-13 by fibroblast-like synoviocytes (FLSs).MethodsThe level of MMP-13 was measured by Western blot and reverse transcriptase polymerase chain reaction (RT-PCR). Expressions of hGITR ligand (hGITRL) on the surface of FLSs and hGITR on the surface of human CD4+ T cells were analyzed by flow cytometry and RT-PCR. Neutralizing antibodies (Abs) were used to block hGITRL and hGITR on the surface of FLSs and human CD4+ T cells, respectively. Human CD4+ T cells were cocultured with FLSs to facilitate interaction between hGITR on CD4+ T cells and hGITRL on FLSs.ResultsSoluble hGITR (shGITR) stimulated FLSs to produce MMP-13, and blockade of hGITRL reduced this effect. Direct contact between activated CD4+ T and FLSs also induced the production of MMP-13, and neutralization of hGITR on activated CD4+ T cells during coculture decreased the amount of MMP-13 produced by FLSs.ConclusionshGITR stimulated FLSs to produce MMP-13 via a signal through hGITRL. Direct contact between activated CD4+ T cells and FLSs facilitated hGITR–hGITRL interaction, and resulted in inducing MMP-13. This effect may increase tissue destruction in chronic inflammation such as rheumatoid arthritis (RA).