Interleukin (IL)4 induces IL6 production by human umbilical vein endothelial cells (HUVEC) in a dose-dependent manner, as shown by bioassay and immunoprecipitation. Interferon (IFN)-gamma, which antagonizes IL4 effects on leukocytes, synergized with IL4 in the induction of IL6 production by HUVEC. Contamination with endotoxin was excluded by heat-inactivated IL4, preincubating with anti-IL4 polyclonal antibody and the use of polymyxin B. The presence of IL4 receptors on HUVEC was shown by affinity cross-linking with 125I-IL4, revealing a 110-kDa binding protein. However, compared with the amount seen on T cells the 60-70-kDa cross-linked doublet was present at much lower levels. Additional lower molecular weight cross-linked proteins were isolated only with HUVEC, but the origin of these is unclear. IL6 is a pluripotent cytokine produced by many cells which promotes the differentiation and growth of lymphocytes and the production of acute phase protein by hepatocytes, and is important in the regulation of immunity at the systemic and local levels. Since IL4 and IFN-gamma are produced by T cells, which are frequently associated with vascular endothelium during chronic inflammation, IL4 is likely to be an important cytokine in the regulation of IL6 and perhaps other cytokine production by endothelium in vivo.