The immunomodulatory potential of thymulin in the perinatal epithelium is not web characterized. In an in vitro model of fetal alveolar type II epithelial cells, we investigated the exhibition of an anti-inflammatory activity of this peptide hormone. Thymulin selectively ameliorated, in a dose-dependent manner, the endotoxin-induced release of IL-1 beta (IC50 = 657 ng.ml(-1)), but showed no inhibitory effect on IL-6 and TNF-alpha. Zinc, an anti-inflammatory antioxidant, which is required for the biological activity of thymulin, reduced the secretion of IL-1 beta (IC50 = 62 mu M), TNF-alpha (IC50 = 1000 mu M), and, to a lesser extent, IL-6. This cation (100 mu M) amplified the effect of thymulin on IL-1 beta and TNF-alpha (IC50 < 0.1 ng.ml(-1)), but not on IL-6. Analysis of whether thymulin is up-regulating a counterpart antiinflammatory signaling loop revealed the involvement of an IL-10-sensitive pathway. These results indicate that thymulin acts as a novel dual immunoregulator by enhancing an anti-inflammatory cytoprotective response and depressing an inflammatory signal, an effect synergistically amplified, in part, by cationic zinc.