Defensins, a family of small, cationic, antimicrobial peptides, are found in mammals, insects and plants. a-defensins are stored in granules of neutrophils and released upon activation by exocytosis. It was shown here that human neutrophil peptide (HNP), at concentrations of 10–8-10–9 M, up-regulated the expression of TNF-a and IL-1b in monocytes activated with Staphylococcus aureus or PMA, while expression of IL-10 mRNA was down-regulated and production of IL-8 was not affected. HNP alone was unable to induce TNF-a or IL-1b expression in resting monocytes. At concentrations of 10–4-10–5 M, HNP was cytotoxic for monocytes in serum-free medium. The cytotoxicity was abrogated in the presence of serum, while a cytokine-modulating effect of HNP was observed in the presence of serum and in whole blood, suggesting that this mechanism may function in vivo. Similarly, serum did not abrogate bactericidal activity of HNP. It was also demonstrated herein that HNP at 10–8-10–9 M, attenuated the inhibitory action of dexamethasone on TNF-a production. In parallel to monocyte studies, we have showed that HNP at concentrations ranging from 10–9 M to 10–6 M caused about 5-fold suppression of VCAM-1 expression in TNF-a-activated human umbilical vein endothelial cells, while the ICAM-1 expression was not affected. Our findings suggest that neutrophil defensins have the potential to modulate the inflammatory responses through regulation of cytokine production and adhesion molecule expression.