Necrotic but not apoptotic cell death releases heat shock proteins, which deliver a partial maturation signal to dendritic cells and activate the NF-kappa B pathway

Dendritic cells (DC) are key components of innate and adaptive immune respo nses, The identity of endogenous signals that activate DC is a crucial and unresolved question. We report here that heat shock proteins (HSP), the mos t abundant and conserved mammalian molecules, constitute such an internal s ignal. Necrotic but not apoptotic cell death leads to release of HSP gp96, calreticulin, hsp90 and hsp70, HSP stimulate macrophages to secrete cytokin es, and induce expression of antigen-presenting and co-stimulatory molecule s on the DC, The HSP gp96 and hsp70 act differentially, and each induces so me but not all molecules. HSP interact with these antigen-presenting cells through the highly conserved NF-kappaB pathway. As HSP are intracellular, a bundant and soluble, their presence in the extra-cellular milieu and the co nsequent activation of antigen-presenting cells (APC) constitutes an excell ent mechanism for response to cell death. As HSP are conserved from bacteri a to mammals, the ability of HSP to activate APC provides a unified mechani sm for response to internal and external stimuli.