Cell contact between T cells and synovial fibroblasts causes induction of adhesion molecules and cytokines

Abstract

Human activated T cells adhere to synovial fibroblast-like cells in vitro. The present study was conducted to investigate the consequences of T cell-synovial fibroblast interactions with regard to induction of adhesion molecules and proinflammatory cytokines. A sensitive Western blot technique, polymerase chain reaction (PCR) amplification, and fluorescence-activated cell sorter (FACS) analysis were used to analyze the induction of VCAM-1 and ICAM-1 expression in T cell-synovial fibroblast cocultures. VCAM-1 and ICAM-1 expression could be induced in synovial fibroblast-like cells by 2 h. PCR amplification showed that both forms of VCAM-1 mRNA are found after the interaction of synovial fibroblasts with T cells. Up-regulation of VCAM-1 and ICAM-1 was confined to synovial fibroblasts; T cells did not express VCAM-1 or increased ICAM-1. In contrast to the T cell-synoviocyte interaction, the interaction between T cells and dermal fibroblasts resulted in the up-regulation of ICAM-1 but not VCAM-1, suggesting tissue-specific regulation of VCAM-1. The T cell-synovial fibroblast interaction also resulted in increased levels of tumor necrosis factor (TNF), interferon-gamma, and interleukin-6 in coculture supernatant. Of the neutralizing antibodies used against these cytokines, only anti-TNF could significantly inhibit VCAM-1 and ICAM-1 expression. When T cells were separated from synoviocytes by a chamber that allowed medium exchange but no cell contact, VCAM-1 and ICAM-1 failed to be up-regulated and cytokine accumulation in cocultures was drastically reduced. Our results demonstrate mutual cell activation of T cells and synoviocytes upon cell contact as shown by the release of T cell- and synoviocyte-specific cytokines and suggest a cell contact-mediated and T cell-initiated mechanism for the chronic accumulation and retention of mononuclear cells via VCAM-1/ICAM-1 by synovial fibroblasts in the rheumatoid synovium.

Interleukin-18 Induces Rheumatoid Arthritis Synovial Fibroblast CXC Chemokine Production through NFκB Activation

“…Actually, a direct effect of IL-18 in IL-8 production is a reasonable explanation, and the early detection (4 and 8 hours) of IL-8 in the conditioned media, as well as in the cytoplasm of RA synovial fibroblasts stimulated with IL-18, strongly supports this hypothesis. Moreover, synovial fibroblasts do not produce TNF-␣ (Bombara et al, 1993;Bucala et al, 1991;Schwachula et al, 1994), even when they are stimulated with lipopolysaccharide (LPS), suggesting that the production of IL-8 by RA synovial fibroblasts is probably linked to a direct effect of IL-18 on these cells. MIP-1␣ is chemotactic for monocytes, whereas ENA-78, gro␣, and IL-8 are important in neutrophil recruitment in the RA joint .…”

Reduction of synovial inflammation after anti‐cd4 monoclonal antibody treatment in early rheumatoid arthritis

“…Presumably, reduction in the number of CD4+ T cells in the synovium results in reduced macrophage activation and cytokine production. Cytokines produced by inflammatory cells up-regulate adhesion molecules, leading to migration into tissues and accumulation of leukocytes and synoviocytes (26)(27)(28). The reduction in cellular infiltration after anti-CD4 therapy may thus be explained by decreased accumulation of inflammatory cells as a result of reduced expression of adhesion molecules.…”

T Cells and Stromal Fibroblasts in Human Tumor Microenvironments Represent Potential Therapeutic Targets

“…For example, skin, bone marrow, and RA synovial fluid fibroblasts all spontaneously make IL-6 [110][111][112]. Increased levels of TNF-α, IL-6, IFN-γ [113] and IL-17A [114] were found when synovial fibroblasts were cultivated with T cells. Dermal fibroblasts also increase their level of IL-6 production when cultivated with T cells and this was even more pronounced with allogeneic cultures than when autologous T cells were used [115].…”

“…For instance, rheumatoid arthritis-derived synovial fibroblasts increased adherence of lymphocytes to endothelial cells while those taken from uninflamed microenvironments (dermal fibroblasts) actually decreased adherence of lymphocytes [125]. Fibroblasts themselves express adhesion molecules with most expressing ICAM-1 particularly in the presence of T cells and with even greater levels of expression in the presence of activated T cells [113].…”