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

Objective: To determine the effect of endothelin-l and endothelin 4 on human monocyte production of cytokines. Design: Previous work from our laboratory has shown that endothelin-l 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-l 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. 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.