subside. Subsequently, levels of HMGB1, a ubiquitously expressed, cytokine-like protein that can activate TLR4 and potentiate cytokine responses, increase about 16 hours after infection and remain elevated for several days (Wang et al. 2001). In mouse models, sepsis-induced death that occurs several days after infection is associated with HMGB1 and is prevented by treatment with antibodies blocking HMGB1. Survivors of sepsis show prolonged increases in serum HMGB1 and cognitive deficits that can be prevented with HMGB1-antibody treatment (Chavan et al. 2012). About half of the patients released from the hospital after surviving a cytokine storm–sepsis insult die within 5 years (Quartin et al. 1997). Thus, innate immune responses can be long lasting and can induce pathology long after they initially have been activated. However, although most studies support a central role for NF-κB–mediated transcription of proinflammatory cytokines, proteases, and oxidases in the innate immune response, both the precise mechanisms that regulate individual cell or cytokine activation and the contributions of tissues and cells in vivo to amplification of specific innate immune genes are poorly understood.
