Interleukin (IL)-6 is important for host defense against various pathogens. The IL-6 receptor (IL-6R) complex consists of a ligand-binding component (IL-6R) and a signal-transducing component (gp130). In a study designed to obtain insight into the regulation of this receptor complex during inflammation, 8 healthy subjects received an intravenous injection of lipopolysaccharide (LPS; 4 ng/kg), and receptor expression was determined on blood leukocytes by use of fluorescence-activated cell cytometry. LPS induced a transient decrease in monocyte and granulocyte IL-6R expression but did not influence gp130. The plasma concentrations of soluble IL-6R and soluble gp130 did not change after LPS administration. Expression of the receptor for leukemia inhibitory factor, a member of the IL-6R family, remained unaltered after LPS injection. In whole blood in vitro, LPS and gram-positive stimuli and proinflammatory cytokines were capable of down-modulating the IL-6R. Monocytes and granulocytes may down-regulate IL-6R at their surface upon their first interaction with bacterial antigens.