Functional CD40 ligand is expressed on human vascular endothelial cells, smooth muscle cells, and macrophages: implications for CD40-CD40 ligand signaling in atherosclerosis

• Published in: Proceedings of the National Academy of Sciences - PNAS 1997-03, Vol.94 (5), p.1931-1936
• Main Authors: Mach, François, Schönbeck, Uwe, Sukhova, Galina K., Bourcier, Todd, Bonnefoy, Jean-Yves, Pober, Jordan S., Libby, Peter
• Format: Article
• Language: English
• Subjects: Antibodies; antigene; antigenos; antigens; Antigens, Differentiation, T-Lymphocyte - metabolism; arn mensajero; arn messager; arteriosclerose; arteriosclerosis; Arteriosclerosis - metabolism; Atherosclerosis; B lymphocytes; B-Lymphocytes - metabolism; Biological Sciences; blood vessels; Blotting, Western; Cardiovascular disease; CD40 Antigens - metabolism; CD40 Ligand; cells; Cells, Cultured; Cellular biology; cellule; celulas; chemoreceptors; chimiorecepteur; Cultured cells; Cytokines; Endothelial cells; Endothelium, Vascular - metabolism; enfermedades vasculares; epitelio; epithelium; expresion genica; expression des genes; Flow Cytometry; gene expression; Gene Expression Regulation; genero humano; genre humain; Humans; Immunity (Disease); Immunohistochemistry; Interferon-gamma - pharmacology; Interleukin-1 - pharmacology; lesion; lesiones; Lesions; Lymphatic system; macrofagos; macrophage; Macrophages; Macrophages - metabolism; maladie vasculaire; mankind; Membrane Glycoproteins - genetics; Membrane Glycoproteins - metabolism; messenger rna; Molecules; muscle; Muscle, Smooth, Vascular - metabolism; muscles; Muscular system; musculos; quimioreceptores; RNA, Messenger - metabolism; Signal Transduction; T lymphocytes; Tumor Necrosis Factor-alpha - pharmacology; vaisseau sanguin; vascular diseases; vasos sanguineos
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.94.5.1931

Increasing evidence supports involvement of inflammation and immunity in atherogenesis. We report here that CD40 ligand (CD40L), an immunoregulatory signaling molecule heretofore considered largely restricted to recently activated CD4+ T lymphocytes, is expressed by human vascular endothelial cells (EC), smooth muscle cells (SMC), and human macrophages in vitro, and is coexpressed with its receptor CD40 on all three cell types in human atherosclerotic lesions in situ. Cultured human vascular EC, SMC, and human macrophages all constitutively expressed CD40L mRNA as well as protein. Stimulation with interleukin 1 beta, tumor necrosis factor alpha, or interferon gamma increased surface levels and de novo synthesis of CD40L on all three cell types. CD40L expressed on EC, SMC, and macrophages exhibited biological activity, as it induced B7.2 expression on B cells. Human vascular SMC also constitutively expressed CD40, the receptor for CD40L, and through CD40 signaling, human recombinant CD40L induced expression of proinflammatory cytokines in these cells, identifying SMC as a target for CD40L. Human atherosclerotic lesions (n = 8) showed expression of immunoreactive CD40L on EC, SMC, and macrophages, while normal arterial tissues (n = 5) contained no CD40L. In atheroma CD40L+ cells often also expressed CD40. These observations establish human vascular EC, SMC, and human macrophages as a novel source of CD40L, and point to T cell-independent CD40 signaling, and a broader function of this pathway in regulation of nonimmune cells, as illustrated here by potential autocrine and paracrine activation during atherogenesis.