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The mechanism by which priming with trehalose 6,6′-dimycolate (TDM, cord factor) induced hypersensitivity to endotoxin lethality was investigated. C57BL/6 and BALB/c mice primed with TDM succumbed to endotoxin shock, but BALB/c IFN-γ knock-out (IFN-γ —/—) mice showed resistance to LPS lethality. The levels of serum IFN-γ peaked on day 4 after priming with TDM and kept significant levels, indicating that IFN-γ plays a critical role for inducing hypersensitivity to LPS lethality. After challenge with LPS, TDM-primed mice produced higher amounts of serum TNFα and soluble CD14. A sulfolipid (SL, 2,3,6,6′-tetraacyl trehalose 2′-sulfate) did not induce the hypersensitivity and, conversely, suppressed the activity of TDM when administered together. Administration of TDM induced infiltration of mononuclear cells in liver, and apoptosis of cells present in the liver sinus was observed after LPS challenge. These results suggest that the hypersensitivity to LPS lethality is due to overproduction of cytokines and other molecules.

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