Toll-like receptors(TLRs) play key roles in the innate immune respons to defense invading microbial pathogens.The identification of the negative regulators and details of the mechanisms by which TLR signaling is fine tuned remain to be fully elucidated.Fas signal can exert non-apoptotic function.We found that Fas signal revealed an inhibitory effect on TLR-initiated inflammatory response in macrophages.The activation MAPKs Erk and P38, NF-κB and IRF3 was inhibitored in macrophages after stimulated with LPS with Fas avtivated antibody(Jo2).And the inhibited role of Fas signaling in TLR signaling did not exist in lpr mice.Fas signal may negatively regulating TLR signaling through non-apoptosis pathway to maintain immunological homeostasis.