MD-2 is a member of the Toll/interleukin-1 receptor (TIR) family, a group of proteins that include the Toll-like receptors (TLRs) (1-3). TLRs are signaling molecules that recognize different pathogen-associated molecular patterns (PAMPs) and serve as an important link between the innate and adaptive immune responses (4). TLR4, the major signaling receptor for lipopolysaccharide (LPS), requires the binding of MD-2 to its extracellular region for maximal response to LPS (5,6). The specificity of this response is determined by the species of MD-2; e.g., human MD-2 can cause mouse TLR4 to react to LPS analogs that are normally antagonistic to human but not mouse TLR4 (7).
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