HSP70 as endogenous stimulus of the Toll/interleukin-1 receptor signal pathway.
Human heat-shock protein (HSP)70 activates innate immune cells and hence requires no additional adjuvants to render bound peptides immunogenic. Here we tested the assumption that endogenous HSP70 activates the Toll/IL-1 receptor signal pathway similar to HSP60 and pathogen-derived molecular patterns. We show that HSP70 induces interleukin-12 (IL-12) and endothelial cell-leukocyte adhesion molecule-1 (ELAM-1) promoters in macrophages and that this is controlled by MyD88 and TRAF6. Furthermore, HSP70 causes MyD88 relocalization and MyD88-deficient dendritic cells do not respond to HSP70 with proinflammatory cytokine production. Using the system of genetic complementation with Toll-like receptors (TLR) we found that TLR2 and TLR4 confer responsiveness to HSP70 in 293T fibroblasts. The expanding list of endogenous ligands able to activate the ancient Toll/IL-1 receptor signal pathway is in line with the "danger hypothesis" proposing that the innate immune system senses danger signals even if they originate from self.
Vabulas
Ramunas M
RM
Institute of Medical Microbiology, Immunology and Hygiene, Technical University of Munich, Trogerstrasse 9, Munich 81675, Germany.
Ahmad-Nejad
Parviz
P
Ghose
Sanghamitra
S
Kirschning
Carsten J
CJ
Issels
Rolf D
RD
Wagner
Hermann
H
D000818:Animals; D002460:Cell Line; D029721:Drosophila Proteins; D004705:Endocytosis; D018840:HSP70 Heat-Shock Proteins / Q000502:physiology*; D006801:Humans; D008262:Macrophage Activation / Q000502:physiology; D008562:Membrane Glycoproteins / Q000378:metabolism*; D051379:Mice; D011956:Receptors, Cell Surface / Q000378:metabolism*; D017472:Receptors, Interleukin-1 / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology*; D051195:Toll-Like Receptor 2; D051197:Toll-Like Receptor 4; D051193:Toll-Like Receptors
D029721:Drosophila Proteins; D018840:HSP70 Heat-Shock Proteins; D008562:Membrane Glycoproteins; D011956:Receptors, Cell Surface; D017472:Receptors, Interleukin-1; C495342:TLR2 protein, human; C495345:TLR4 protein, human; D051195:Toll-Like Receptor 2; D051197:Toll-Like Receptor 4; D051193:Toll-Like Receptors