MD-2, a Novel Accessory Molecule, Is Involved in Species-Specific Actions ofSalmonellaLipid A

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Abstract
Salmonellalipid A is inactive in human macrophages despite being potently active in murine macrophages. We investigated the molecular basis for this species-specific action ofSalmonellalipid A. When murine CD14 (mCD14), mTLR4, and mMD-2 were all expressed in human monocytic THP-1 cells, these cells were capable of responding toSalmonellalipid A. Expressing each of these proteins separately did not impart such responsiveness. Expression of mTLR4 plus mMD-2, but not mCD14 plus mTLR4 or mCD14 plus mMD-2, conferred this responsiveness. In THP-1 cells expressing mCD14, mTLR4, and mMD-2, replacing mCD14 with human CD14 had no effect on responsiveness toSalmonellalipid A or syntheticSalmonella-type lipid A (compound 516). When mTLR4 was replaced with human TLR4, the responses to these lipid A preparations were decreased to half, and the replacement of mMD-2 decreased responsiveness to one-third, although the responses toEscherichia colilipid A or syntheticE. coli-type lipid A (compound 506) were not affected. These results indicate that both TLR4 and MD-2 participate in the species-specific action ofSalmonellalipid A.