Differential role of interferon-gamma in the potentiating effect of muramyl peptides for enhanced responses to lipopolysaccharide in mice: effect of cyclosporin A.

Cyclosporin A (CsA) administration reduced mortality in mice sensitized to endotoxic toxicity by various agents, such as muramyl dipeptide (MDP) or a lipophilic derivative. CsA is an inhibitor of a variety of T cell responses, suggesting that muramyl peptides could influence LPS-induced effects via the release of lymphokine. The potentiation of TNF production by pretreatment with muramyl peptides was comparable in nude mice and in controls, indicating that it is a T-independent mechanism, and CsA produced a similar inhibition in both groups. Neutralizing antibody to IFN-gamma did not change the elevated TNF level obtained in the blood when LPS was given after a muramyl peptide. However, the same treatment with anti-IFN-gamma MAb prevented the death of mice challenged with LPS plus MDP or plus a lipophilic derivative displaying similar effects. In comparing three selected muramyl peptides, we also show that the priming effect could be dissociated from the toxic synergism with LPS.