Human peripheral monocytes were stimulated with opsonized zymosan or protein A-containing Staphylococcus aureus to examine whether factors might be released that were capable of stimulating mucous glycoprotein release from cultured human airways, as has recently been described with human pulmonary macrophages. While the supernatant from monocytes exposed to opsonized zymosan or protein A-containing S. aureus caused an impressive activity was found in the control samples that were cultured in parallel and exposed to nonactivated zymosan or S. aureus that was deficient in protein A. The responsible factor was termed monocyte-derived mucus secretagogue (MMS). The maximum MMS release was reached 4-8 h after stimulation, and the amount of MMS released was dependent on the dose of opsonized zymosan added. Chromatographic analyses of MMS indicate that its molecular weight was approximately 2,000 and that the isoelectric point (pI) was 5.2, with a smaller second peak of 7.4 on isoelectric focusing. MMS itself was not detected in monocyte lysates, nor was it formed by monocytes treated with the protein synthesis inhibitor, cycloheximide, before exposure to activating particles. MMS was not a prostaglandin, could not be extracted into organic solvents, and is probably not an eicosanoid. Based on these observations, we conclude that stimulated human peripheral monocytes synthesize a small, acidic molecule, termed MMS, that is capable of stimulating human airways to secrete mucus and in nearly every respect is identical to pulmonary macrophage-derived MMS.