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

Abstract

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 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␤, tumor necrosis factor ␣, or interferon ␥ 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.

Induction of triggering receptor expressed on myeloid cells 1 in murine resident peritoneal macrophages by monosodium urate monohydrate crystals

“…Activation of CD40 by binding to CD40 ligand amplifies the production of proinflammatory cytokines by macrophages (24), while ICAM is an adhesion molecule that facilitates recruitment of neutrophils and macrophages to inflammation foci. Thus, induction of these molecules by TREM-1 may lead to initiation of the inflammatory response in acute gout (25).…”

IFN Regulatory Factor-1 Is Required for the Up-Regulation of the CD40-NF-κB Activator 1 Axis During Airway Inflammation

“…The primary action of CD40-mediated pathway was thought to be restricted to thymus-dependent humoral responses (1). However, a variety of nonlymphocytic cell types have also been shown to express CD40, including monocytes, basophils, dendritic cells, fibroblasts, smooth muscle cells, endothelial cells, and epithelial cells (2)(3)(4)(5). Studies from many groups indicate that CD40 probably plays a more general role in immune regulation (6).…”

Analysis of Intragraft Gene and Protein Expression of the Costimulatory Molecules, CD80, CD86 and CD154, in Orthotopic Liver Transplant Recipients

“…Such surface molecules include the contact-dependant CD40-CD154 costimulatory pathways. Endothelial expression of CD154 has previously been described in human cardiac allografts during episodes of ACR (8), and in renal allografts during ACR and CR (6,10,25,26). Although all these studies have demonstrated an increased expression of CD154 during allograft rejection, there have not been, to our knowledge, any experimental studies identifying the specific role of CD40-mediated signalling on endothelium.…”