Nf-κb Action in Sepsis: the Innate Immune System and the Heart

Sepsis is the clinical syndrome that results from a host’s inflammatory response to infection via activation of the innate immune system. This response involves a complex network of inflammatory mediators that is selfreinforcing. When this immune response progresses uncontrollably, it can ultimately result in cardiovascular collapse and death. This complex inflammatory response is comprised of multiple mediators including cytokines such as TNF-α and IL-1β, that are synthesized and secreted in response to signaling by receptors of the Toll-like receptor (TLR) family of pattern recognition receptors (PRR) that bind to pathogen associated molecules. A central downstream element of TLR-dependent signaling is the pleiotropic transcription factor NF-κB. NF-κB has been implicated in the regulation of multiple biological phenomena and disease states, including apoptosis, cell growth, stress response, innate immunity and septic shock. NF-κB-dependent genes are numerous and several have been implicated in the pathogenesis of sepsis and associated with cardiac dysfunction in sepsis. NF-κB activation occurs in multiple organs and cell types, and may be primarily protective in one tissue but injurious in another. Thus, a detailed understanding of the molecular basis of the pathophysiology of sepsis is needed in order to specifically block pro-inflammatory and pro-apoptotic signaling in the heart, while avoiding adverse effects in other organs.