Additionally, HMGB1 has been shown to play a central role in the initiation and propagation of the inflammatory response following traumatic injury. In a mouse femur fracture model, administration of neutralizing HMGB1 antibodies results in decreased serum IL-6 and IL-10 levels. This blunted systemic response corresponds with decreased hepatic and gut barrier dysfunction as measured by serum transaminase levels and NF-κB activation, respectively. Interestingly, the contribution of HMGB1 to end organ injury in this model appears once again to be TLR4 dependent, as mutants are protected when compared with wild-types. No additional protec-tion is seen when antibodies are administered to TLR4 mutants (116) .