Editors' ChoiceInnate Immunity

Hsp70 Signals Danger

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Science's STKE  30 Apr 2002:
Vol. 2002, Issue 130, pp. tw158
DOI: 10.1126/stke.2002.130.tw158

The ability of invariant molecular structures derived from foreign agents to activate the innate immune system through the Toll-like receptor (TLR) pathway is well established. A theory that is emerging is that the innate immune system may also be activated by endogenous ligands released from cells during necrotic cell death, thus producing a "danger" signal for the immune system. Asea et al. and Vabulas et al. both show that the TLR2 and TLR4 are able to transduce a signal upon treatment of cells with the heat shock protein Hsp70. The pathway activated by Hsp70 depended on the TLR adaptor MyD88 and required the presence of a coreceptor, either CD14 or MD-2. Both groups reported that Hsp70 activated dendritic cells and could stimulate the TLR pathway in human embryonic kidney cells (HEK 293) transfected with the TLRs and a coreceptor. Although the true test of this concept of the danger signal awaits an in vivo assay, the idea of the release of signaling factors by dying cells is an intriguing one.

A. Asea, M. Rehli, E. Kabingu, J. A. Boch, O. Baré, P. E. Auron, M. A. Stevenson, S. K. Calderwood, Novel signal transduction pathway utilized by extracellular HSP70: Role of Toll-like receptor (TLR) 2 and TLR4. J. Biol. Chem. 277, 15028-15034 (2002). [Abstract] [Full Text]

R. M. Vabulas, P. Ahmad-Nejad, S. Ghose, C. J. Kirschning, R. D. Issels, H. Wagner, HSP70 as endogenous stimulus of the Toll/Interleukin-1 receptor signal pathway. J. Biol. Chem. 277, 15107-15112 (2002). [Abstract] [Full Text]

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