Endocytosed HSP60s use toll-like receptor 2 (TLR2) and TLR4 to activate the toll/interleukin-1 receptor signaling pathway in innate immune cells.
Heat shock proteins (HSPs) require no adjuvant to confer immunogenicity to bound peptides, as if they possessed an intrinsic "danger" signature. To understand the proinflammatory nature of HSP, we analyzed signaling induced by human and chlamydial HSP60. We show that both HSP60s activate the stress-activated protein kinases p38 and JNK1/2, the mitogen-activated protein kinases ERK1/2, and the I-kappaB kinase (IKK). Activation of JNK and IKK proceeds via the Toll/IL-1 receptor signaling pathway involving MyD88 and TRAF6. Human fibroblasts transfected with TLR2 or TLR4 plus MD-2 gain responsiveness to HSP60, while TLR2- or TLR4-defective cells display impaired responses. Initiation of signaling requires endocytosis of HSP60 that is effectively inhibited by serum component(s). The results revealed that adjuvanticity of HSP60 operates similar to that of classical pathogen-derived ligands.
Vabulas
R M
RM
Institute of Medical Microbiology, Immunology and Hygiene, Technical University of Munich, Trogerstr. 9, 81675 Munich, Germany.
Ahmad-Nejad
P
P
da Costa
C
C
Miethke
T
T
Kirschning
C J
CJ
Häcker
H
H
Wagner
H
H
D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D000943:Antigens, Differentiation / Q000502:physiology; D001426:Bacterial Proteins; D002460:Cell Line; D018834:Chaperonin 60; D018833:Chaperonins / Q000378:metabolism*; D029721:Drosophila Proteins; D004705:Endocytosis; D006801:Humans; D008562:Membrane Glycoproteins / Q000502:physiology*; D051379:Mice; D053594:Myeloid Differentiation Factor 88; D011506:Proteins / Q000502:physiology; D011956:Receptors, Cell Surface / Q000502:physiology*; D011971:Receptors, Immunologic; D017472:Receptors, Interleukin-1 / Q000502:physiology*; D048029:TNF Receptor-Associated Factor 6; D051195:Toll-Like Receptor 2; D051197:Toll-Like Receptor 4; D051193:Toll-Like Receptors; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis
D048868:Adaptor Proteins, Signal Transducing; D000943:Antigens, Differentiation; D001426:Bacterial Proteins; D018834:Chaperonin 60; D029721:Drosophila Proteins; C507779:MYD88 protein, human; D008562:Membrane Glycoproteins; C507780:Myd88 protein, mouse; D053594:Myeloid Differentiation Factor 88; D011506:Proteins; D011956:Receptors, Cell Surface; D011971:Receptors, Immunologic; D017472:Receptors, Interleukin-1; C495342:TLR2 protein, human; C495345:TLR4 protein, human; D048029:TNF Receptor-Associated Factor 6; D051195:Toll-Like Receptor 2; D051197:Toll-Like Receptor 4; D051193:Toll-Like Receptors; D014409:Tumor Necrosis Factor-alpha; C074119:heat-shock protein 65, Mycobacterium; D018833:Chaperonins