Endothelin-1 and endothelin-4 stimulate monocyte production of cytokines

OBJECTIVE To determine the effect of endothelin-1 and endothelin-4 on human monocyte production of cytokines. DESIGN Previous work from our laboratory has shown that endothelin-1 activates leukocytes. Endothelin-1 and endothelin-3 are principally produced by vascular endothelium. However, epidermal cells in gut mucosa, lung, and kidney produce endothelin-2 and endothelin-4, which differ by a single amino acid. While structurally similar to endothelin-1, endothelin-2 and endothelin-4 may affect gut smooth muscle and other tissues differently. The effect of endothelin-1 and endothelin-4 was examined on monocyte production of interleukins (IL) and neutrophil activation factors. SETTING A clinically-oriented basic science laboratory in a Veteran's Administration Hospital and Medical Center. SUBJECTS Healthy volunteer adult male/female medical students, researchers, and hospital workers. INTERVENTIONS Human peripheral blood mononuclear cells were separated on density gradients and cultured in media, with or without the addition of bacterial endotoxin or varying molar concentrations of endothelin-1 and endothelin-4. Supernatants were harvested at 10 mins, and at 1, 6, 12, 24, and 48 hrs, and enzyme-linked immunosorbent assays were performed to determine the presence of tumor necrosis factor-alpha, IL-1 beta, IL-6, IL-8, and granulocyte-macrophage colony-stimulating factor. MEASUREMENTS AND MAIN RESULTS Endothelin-1 and endothelin-4 were potent stimuli for monocyte production of tumor necrosis factor-alpha, IL-8, and granulocyte-macrophage colony-stimulating factor. They also caused IL-1 beta and IL-6 production. CONCLUSION Endothelin-1 and endothelin-4 may activate leukocytes after shock or gut ischemia, resulting in further injury to reperfused tissues and distant injury to lungs and other organs. Crit Care Med 1997; 25:958-964)