FUNCTIONAL CD40 LIGAND IS EXPRESSED ON HUMAN VASCULAR ENDOTHELIAL-CELLS, SMOOTH-MUSCLE CELLS, AND MACROPHAGES - IMPLICATIONS FOR CD40-CD40 LIGAND SIGNALING IN ATHEROSCLEROSIS

Increasing evidence supports involvement of inflammation and immunity in atherogenesis. We report here that CD40 ligand (CD?OL), an immunore gulatory signaling molecule heretofore considered largely restricted t o recently activated CD4(+) T lymphocytes, is expressed by human vascu lar endothelial cells (EC), smooth muscle cells (SMC), and human macro phages in vitro, and is coexpressed with its receptor CD40 on all thre e cells 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, tu mor necrosis factor alpha, or interferon gamma increased surface level s and de novo synthesis of CD40L on all three cell types. CD40L expres sed on EC, SMC, and macrophages exhibited biological activity, as it i nduced B7.2 expression on B cells, Human vascular SMC also constitutiv ely expressed CD40, the receptor for CD40L, and through CD40 signaling , human recombinant CD40L induced expression of proinflammatory cytoki nes in these cells, identifying SMC as a target for CD40L. Human ather osclerotic lesions (n = 8) showed expression of immunoreactive CD40L o n EC, SMC, and macrophages, while normal arterial tissues (n = 5) cont ained no CD40L. In atheroma CD40L(+) cells often also expressed CD40, These observations establish human vascular EC, SMC, and human macroph ages as a novel source of CD40L, and point to T cell-independent CD40 signaling, and a broader function of this pathway in regulation of non immune cells, as illustrated here by potential autocrine and paracrine activation during atherogenesis.