SUMMARYHuman lung alveolar epithelial cells constitutively express class II major histocompatibility complex ( MHC). Human lung microvascular endothelial and small airway epithelial cells can be induced to express class II MHC by stimulation with the pro-inflammatory cytokine interferonc. The levels of class II MHC on lung epithelial and endothelial cells were comparable to those seen on an Epstein-Barr virus (EBV )-transformed B-cell line. However, the costimulatory molecules B7-1 and B7-2 were not expressed. The ability of the class II MHC expressing human lung parenchymal cells to present alloantigen to CD4+ T lymphocytes was investigated. Freshly isolated human alveolar epithelial cells (type II pneumocytes) and monolayers of interferon-cstimulated small airway epithelial and lung microvascular endothelial cells were co-cultured with allogeneic CD4+ T lymphocytes and proliferation determined by [3H ]thymidine incorporation. A clear diÂerence was observed between eÂects of the epithelial and endothelial cells on CD4+ T-lymphocyte activation. Alveolar and small airway epithelial cells failed to stimulate the proliferation of allogeneic CD4+ T lymphocytes whereas lung microvascular endothelial cells did stimulate proliferation. This diÂerence could not be explained by the levels of class II MHC or the lack of B7-1 and B7-2 solely. Microvascular endothelial cells, and not alveolar or small airway epithelial cells, possess B7-independent costimulatory pathways.

SUMMARYHeparin is a polyanionic glycosaminoglycan (GAG) that can bind with high affinity to a range of cytokines including interferon-c (IFN-c) and members of the chemokine superfamily. This GAG also possesses immunomodulatory activity in vivo and can antagonize the capacity of IFN-c to induce class II MHC antigen expression, and to up-regulate intercellular adhesion molecule-1, by cultured endothelial cells. Previous studies have shown that binding to cell-surface heparan sulphate is essential for optimal activity of IFN-c and that free heparin competitively inhibits this sequestration process. The present study was performed to increase our understanding of the immunosuppressive activity of heparin by investigation of potential antagonism of the production and function of monocyte chemotactic peptide-1 (MCP-1), a chemokine important for mononuclear leucocyte recruitment across vascular endothelium. It was found that mixture of heparin with IFN-c inhibited up-regulation of the signal transducer and activator of transcription protein, STAT-1 produced normally by treatment of endothelial cells with IFN-c. An inhibition of MCP-1 production was observed that was specifically caused by mixture of IFN-c with heparin-like, and therefore cytokine-binding, GAGs. It was also shown that mixture of heparin-like GAGs with MCP-1 inhibited the rapid tyrosine phosphorylation of phosphatidylinositol 3-kinase which is normally produced by treatment of mononuclear leucocytes with this chemokine. Blockade of this intracellular signalling event was associated with a reduction in the normal transendothelial migration response towards MCP-1. Results from this study indicate that soluble, heparin-like GAGs can block IFN-c-dependent up-regulation of MCP-1 production by cultured endothelial cells, and can also antagonize the leucocyte-activating and migration-promoting properties of pre-existing MCP-1. These activities may contribute to the immunomodulatory properties of heparin. INTRODUCTIONand phagocyte-activating properties.1 A further effect of IFN-c is to augment the potential immunogenicity of a variety of Interferon-c (IFN-c) is an important proinflammatory cells, such as those of vascular endothelium.2 Specific effects cytokine, playing a central role in immune and inflammatory on endothelial cells include up-regulation of the expression of responses. This pleiotropic molecule is produced by activated adhesion molecules, such as intercellular adhesion molecule-1 CD8+ and Th1-type CD4+ T cells, and possesses anti-viral (ICAM-1), and class I major histocompatibility complex (MHC ) antigens3 and the induction of class II MHC antigens.

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