MyD88–BLT2-dependent cascade contributes to LPS-induced interleukin-6 production in mouse macrophage

Endotoxic responses to bacterial lipopolysaccharide (LPS) are triggered by Toll-like receptor 4 (TLR4) and involve the production of inflammatory mediators, including interleukin-6 (IL-6), by macrophages. The detailed mechanism of IL-6 production by macrophages in response to LPS has remained unclear, however. We now show that LPS induces IL-6 synthesis in mouse peritoneal macrophages via the leukotriene B4 receptor BLT2. Our results suggest that TLR4–MyD88 signaling functions upstream of BLT2 and that the generation of reactive oxygen species (ROS) by NADPH oxidase 1 (Nox1) and consequent activation of the transcription factor nuclear factor (NF)-κB function downstream of BLT2 in this response. These results suggest that a TLR4–MyD88–BLT2–Nox1–ROS–NF-κB pathway contributes to the synthesis of IL-6 in LPS-stimulated mouse macrophages. A cascade of receptor binding and signaling systems allows bacterial endotoxins to cause dangerous inflammatory responses. Endotoxins, consisting of linked lipid and polysaccharide, are released from some bacterial cell walls when the bacteria begin to break down. They can stimulate excessive and potentially fatal blood poisoning and "endotoxic shock". This damaging process is mediated by the release of signaling molecules, including immune system proteins known as interleukins, by cells that the toxins bind to. Jae-Hong Kim and co-workers at Korea University in Seoul, South Korea, have uncovered key steps in the pathway leading to interleukin-6 release when the toxins bind to certain mouse white blood cells. These findings could contribute to understanding and prevention of the endotoxic shock that is a leading cause of death in critically ill patients.