Fibroblasts from different sites may promote or inhibit recruitment of flowing lymphocytes by endothelial cells

Abstract

We examined the hypothesis that stromal fibroblasts modulate the ability of endothelial cells (EC) to recruit lymphocytes in a site-specific manner. PBL were perfused over HUVEC that had been cultured with fibroblasts isolated from the inflamed synovium or the skin of patients with rheumatoid arthritis or osteoarthritis, or from normal synovium, with or without exposure to the inflammatory cytokines TNF-α+IFN-γ. Fibroblasts from inflamed synovium, but no others, caused unstimulated HUVEC to bind flowing lymphocytes. This adhesion was supported by α4β1-VCAM-1 interaction and stabilised by activation of PBL through CXCR4–CXCL12. Antibody neutralisation of IL-6 during co-culture effectively abolished the ability of EC to bind lymphocytes. Cytokine-stimulated EC supported high levels of lymphocyte adhesion, through the presentation of VCAM-1, E-selectin and chemokine(s) acting through CXCR3. Interestingly, co-culture with dermal fibroblasts caused a marked reduction in cytokine-induced adhesion, while synovial fibroblasts had variable effects depending on their source. In the dermal co-cultures, neutralisation of IL-6 or TGF-β caused partial recovery of cytokine-induced lymphocyte adhesion; this was complete when both were neutralised. Exogenous IL-6 was also found to inhibit response to TNF-α+IFN-γ. Normal stromal fibroblasts appear to regulate the cytokine-sensitivity of vascular endothelium, while fibroblasts associated with chronic inflammation bypass this and develop a directly inflammatory phenotype. Actions of IL-6 might be pro-inflammatory or anti-inflammatory, depending on the local milieu.

Prostaglandin D2 Regulates CD4+ Memory T Cell Trafficking across Blood Vascular Endothelium and Primes These Cells for Clearance across Lymphatic Endothelium

“…In agreement with previous observations (7,8), we found that a function-blocking Ab against CXCR3 nearly abolished the adhesion of flowing PBL to TNF-and IFN-stimulated EC (Fig. 2A).…”

“…There is also a strong presumption that chemokine signals are sufficient to promote lymphocyte migration over and through the endothelial monolayer and into inflamed tissue. In the case of EC treatment with TNF plus IFN, chemokines acting through the lymphocyte-borne receptor CXCR3 have been shown to stabilize attachment, but the signals inducing transendothelial migration have not been defined (7,8). Transendothelial migration of T cells has been observed within minutes of adhesion to EC activated with TNF (where blockade of b 2 integrins was inhibitory) (4), with TNF plus IFN (7), and for EC stimulated with TNF and to which stromal-derived factor-1a (CXCL12) or CCL19 (ELC) had been added to the EC surface (9).…”

Contribution of Human Fibroblasts and Endothelial Cells to the Hallmarks of Inflammation as Determined by Proteome Profiling

“…This molecule is regulated by other components of the ECM such as TSP1 and tumor necrosis factor-inducible gene 6 protein (TSG6) (60). These two proteins were presently observed to be up-regulated in stimulated NHDF, indicating that fibroblasts may be involved in regulating the recruitment of leukocytes by endothelial cells during inflammation, which was also observed by McGettrick et al (61). Such interrelations between angiogenesis and ECM reorganization as well as between fibroblasts and endothelial cells are further demonstrated by the interrelation of two important proteins mentioned before, PRRX1 and TNC.…”

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

“…The manner in which fibroblasts alter the adhesiveness of endothelial cells has been shown to be in part dependent upon the milieu from which the fibroblast was derived. 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].…”