Increase in proliferation and cytotoxic cell development in human mixed lymphocyte cultures in the presence of very low concentrations of LPS: role of IL-1 and prostaglandin E2.

Lipopolysaccharide (LPS) added to human allogeneic mixed lymphocyte cultures (MLC), even at very low concentrations, increased the level of specific cytotoxicity that developed. Proliferation was also increased by LPS in MLC but no increase was detectable when the allogeneic stimulus was absent. LPS enhanced only low cytotoxic responses while having little effect on naturally high responses. Significant enhancement in cytotoxic response was found within the picogram-nanogram per milliliter range of concentrations of LPS and only when it was added at the initiation of cultures. This early action of low concentrations of LPS suggested that IL-1 was involved. Indeed, a supernatant from silica-treated human mononuclear cells containing IL-1 activity also enhanced cytotoxic and proliferative responses. Aside from increasing IL-1 secretion we also found that LPS significantly increased synthesis and secretion of PGE2 which had a selective inhibitory effect. Namely, addition of indomethacin or flurbiprofen to MLC further enhanced the cytotoxicity of LPS-treated but not that of untreated cultures without increasing the proliferative response. These results suggest a key role for macrophage-derived IL-1 and PGE2 in the regulation of proliferative and cytotoxic responses of T cells. They also suggest that very low amount of LPS may reach the immune system and contribute to the expression of cell-mediated immune responses.