International Immunology, Vol. 12, No. 11, 1539-1546,
November 2000
© 2000 Japanese Society for Immunology
Necrotic but not apoptotic cell death releases heat shock proteins, which deliver a partial maturation signal to dendritic cells and activate the NF-
B pathway
Center for Immunotherapy of Cancer and Infectious Diseases, University of Connecticut School of Medicine, MC1601, Farmington, CT 06030-1601, USA
Correspondence to: P. K. Srivastava
Dendritic cells (DC) are key components of innate and adaptive immune responses. The identity of endogenous signals that activate DC is a crucial and unresolved question. We report here that heat shock proteins (HSP), the most abundant and conserved mammalian molecules, constitute such an internal signal. Necrotic but not apoptotic cell death leads to release of HSP gp96, calreticulin, hsp90 and hsp70. HSP stimulate macrophages to secrete cytokines, and induce expression of antigen-presenting and co-stimulatory molecules on the DC. The HSP gp96 and hsp70 act differentially, and each induces some but not all molecules. HSP interact with these antigen-presenting cells through the highly conserved NF-
B pathway. As HSP are intracellular, abundant and soluble, their presence in the extra-cellular milieu and the consequent activation of antigen-presenting cells (APC) constitutes an excellent mechanism for response to cell death. As HSP are conserved from bacteria to mammals, the ability of HSP to activate APC provides a unified mechanism for response to internal and external stimuli.
Keywords: cytokines, hsp70, hsp90, innate immunity, gp96
1 Present address: Apt A101 Osaki Houfu, Yamaguchi 747, Japan.
Transmitting editor: S. H. E. Kaufmann
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