Cytokine production induced via CD14-dependent and CD14-independent pathways was investigated in mouse peritoneal macrophages incubated with lipopolysaccharide (LPS) or lipid A. Different LPS receptors appear to be responsible for production of tumour necrosis factor-alpha (TNF-alpha) and interleukin-1 alpha (IL-1 alpha) and IL-1 beta. TNF-alpha production is essentially CD14 dependent, both in the presence or absence of plasma. In the presence of plasma, endotoxin-induced IL-1 production is mediated by CD14-dependent mechanisms, while in its absence both CD14-dependent and CD14-independent pathways are involved. Lipid A stimulates cytokine synthesis through both CD14-dependent and CD14-independent mechanisms, but its action is weaker than that of LPS, indicating that the polysaccharide moiety may be necessary for proper stimulation of mouse macrophages by endotoxin.