Methionine enkephalin (Met-Enk), the endogenous neuropeptide, is suggested to be involved in the regulatory loop between immune and neuroendocrine systems. Our studies showed that Met-Enk over a wide range of concentrations increased interleukin-1 (IL-1) production from mouse peritoneal macrophages induced by lipopolysaccharides (LPS) and naloxone did not block the enhancing effect. Met-Enk promoted the proliferation of mouse splenocyte and the production of IL-2 and IL-6 in a dose-dependent manner. The up-regulating effects of IL-2 and IL-6 not only augmented their mRNA transcription but also increased their stability. Thus Met-Enk appears to be an important immunomodulatory signaling molecule to exert regulatory actions concerned with the expressing of pre-inflammatory cytokines.