inflammation ͉ intracellular calcium

C‐terminal‐binding protein/brefeldin A‐ADP ribosylated substrate (CtBP/BARS) plays key roles in development and oncogenesis as a transcription co‐repressor, and in intracellular traffic as a promoter of Golgi membrane fission. Co‐repressor activity is regulated by NAD(H) binding to CtBP/BARS, while membrane fission is associated with its acyl‐CoA‐dependent acyltransferase activity. Here, we report the crystal structures of rat CtBP/BARS in a binary complex with NAD(H), and in a ternary complex with a PIDLSKK peptide mimicking the consensus motif (PXDLS) recognized in CtBP/BARS cellular partners. The structural data show CtBP/BARS in a NAD(H)‐bound dimeric form; the peptide binding maps the recognition site for DNA‐binding proteins and histone deacetylases to an N‐terminal region of the protein. The crystal structure together with the site‐directed mutagenesis data and binding experiments suggest a rationale for the molecular mechanisms underlying the two fundamental co‐existing, but diverse, activities supported by CtBP/BARS in the nucleus and in Golgi membranes.

Systemic sclerosis is an autoimmune disease characterized by immunological and vascular abnormalities. Autoantibodies against intracellular antigens are associated with particular clinical features of the disease, whereas autoantibodies against cell surface antigens may be pathogenic by inducing endothelial cell damage, considered the primary event in the pathogenesis of the disease. Latent human cytomegalovirus infection may contribute to progression of systemic sclerosis through its ability to infect endothelial cells; however, direct links between human cytomegalovirus infection and systemic sclerosis are still lacking. Molecular mimicry is one of the mechanisms that account for the link between infection and autoimmunity. Here we have identified an immunodominant peptide using systemic sclerosis serum screening of a random peptide library; such peptide shares homology with autoantigens and with the human cytomegalovirus late protein UL94 (ref. 9). Immunoglobulin G antibodies against the peptide affinity-purified from the sera of patients with systemic sclerosis specifically recognized the viral product and autoantigens; moreover, such antibodies induced endothelial cell apoptosis through specific interaction with the cell surface integrin-NAG-2 protein complex. Our results provide evidence that antibodies against human cytomegalovirus cause apoptosis of endothelial cells, considered the initial pathogenic event of systemic sclerosis, and indicate a previously unknown mechanism for the etiological link between human cytomegalovirus infection and autoimmunity.

HLA-E-restricted T cell receptor ␣␤ ؉ CD8 ؉ cytolytic T lymphocytes (CTLs) exist as monoclonal expansions in the peripheral blood of some individuals. Here, we show that they recognize, with high avidity, peptides derived from the UL40 protein of different human cytomegalovirus (CMV) strains. Recognition results in the induction of cytotoxicity, IFN-␥ production and cell proliferation. Autologous cells pulsed with CMV-derived peptides become susceptible to lysis by HLA-E-restricted CTLs and induce their proliferation. The high avidity for CMV-derived peptides may explain how these cells are generated in vivo and suggest their possible role in the host defenses against CMV, a virus that evolved various mechanisms to down-regulate classical HLA class I molecules, thus escaping detection by conventional CTLs.

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Human mesenchymal stem cells (MSC) are immunosuppressive and poorly immunogenic but may act as antigen-presenting cells (APC) for CD4؉ T-cell responses; here we have investigated their ability to serve as APC for in vitro CD8

Abscisic acid (ABA) is a phytohormone recently identified as a new endogenous pro-inflammatory hormone in human granulocytes. Here we report the functional activation of human monocytes and vascular smooth muscle cells by ABA. Incubation of monocytes with ABA evokes an intracellular Ca 2؉ rise through the second messenger cyclic ADP-ribose, leading to NF-B activation and consequent increase of cyclooxygenase-2 expression and prostaglandin E 2 production and enhanced release of MCP-1 (monocyte chemoattractant protein-1) and of metalloprotease-9, all events reportedly involved in atherogenesis. Moreover, monocytes release ABA when exposed to thrombin-activated platelets, a condition occurring at the injured vascular endothelium; monocyte-derived ABA behaves as an autocrine and paracrine pro-inflammatory hormone-stimulating monocyte migration and MCP-1 release, as well as vascular smooth muscle cells migration and proliferation. These results, and the presence of ABA in human arterial plaques at a 10-fold higher concentration compared with normal arterial tissue, identify ABA as a new signal molecule involved in the development of atherosclerosis and suggest a possible new target for anti-atherosclerotic therapy. ABA2 is an isoprenoid phytohormone regulating several physiological functions in Metaphyta, including response to abiotic stress (1), and in lower Metazoa, where ABA mediates temperature-induced oxygen consumption and water filtration in sponges (2) Monocytes play a key role in both inflammation and immunity by performing antigen presentation, phagocytosis, and immunomodulation through the production of various cytokines and growth factors (6). In atherosclerosis, a chronic immune inflammatory disease, the interaction between monocytes, platelets, and injured luminal endothelium is a crucial event leading to the atherosclerotic lesion of the arterial intima (7,8). Platelets trigger atherogenesis through adhesion to damaged endothelial cells and release of pro-inflammatory mediators, recruiting circulating monocytes to the site of the lesion (9). Monocytes attach to and penetrate the vessel wall, where they undergo transformation into macrophages and eventually into foam cells (10). At the site of the atherosclerotic lesion, monocytes/macrophages, platelets, and endothelial cells release chemoattractants, growth factors, and cytokines, which stimulate VSMC proliferation and migration into the sub-endothelium. Thrombus organization, extracellular matrix synthesis, and VSMC proliferation eventually lead to the development of the atheromatous plaque (7-10). Here we investigate the effect of ABA on human monocytes and VSMC and its possible role in the activation of cell responses known to be responsible for atherogenesis.