Monocyte chemoattractant protein-1 (MCP-1) is a protective cytokine in murine endotoxaemia induced by lipopolysaccharide (LPS). In this study, LPS-induced pathophysiology in the human (h) MCP-1 transgenic mouse (Tgm) line was investigated. The hMCP-1 Tgm showed a marked increase in the mortality and weight loss following LPS administration. In the Tgm spleens, disappearance of marginal zone macrophages (MZMphi) and dendritic cells (DC) was induced by a smaller amount of LPS than that required for the disappearance in non-transgenic littermates. A significant number of apoptotic cells were seen in these areas. Furthermore, expressions of tumour necrosis factor-alpha (TNF-alpha), interleukin-1alpha (IL-1alpha), and IL-6 mRNA were enhanced and sustained in the LPS-treated Tgm. Neutralization of TNF-alpha considerably depressed the LPS-sensitivity of Tgm. These findings demonstrate that the continuous and systemic presence of MCP-1 is no more protective toward endotoxaemia and suggest that the high sensitivity of the MZMphi and DC to LPS is attributed to the enhanced TNF-alpha production in the hMCP-1 Tgm.