Endocytosed HSP60s Use Toll-like Receptor 2 (TLR2) and TLR4 to Activate the Toll/Interleukin-1 Receptor Signaling Pathway in Innate Immune Cells

Institute of Medical Microbiology, Immunology and Hygiene, Technical University of Munich, Trogerstr. 9, 81675 Munich, Germany.
Journal of Biological Chemistry (Impact Factor: 4.57). 09/2001; 276(33):31332-9. DOI: 10.1074/jbc.M103217200
Source: PubMed


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.

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    • "Several DAMPs are released after CNS injury and are known ligands for a range of TLRs (Table 1). These include HMGB1, heat-shock proteins (HSP60 and HSP70), degradation products of the ECM (hyaluronic acid, fibronectin) and nucleic acids such as mRNA and miRNAs that are released passively from necrotic cells (Asea et al., 2002; Demarco et al., 2005; Kariko et al., 2004; Li et al., 2001; Ohashi et al., 2000; Okamura et al., 2001; Park et al., 2004; Smiley et al., 2001; Termeer et al., 2002; Vabulas et al., 2001, 2002; Yu et al., 2006). Mitochondrial DNA and proteins also act as DAMPs, particularly mtDNA and N-formyl peptides (Zhang et al., 2010) (Table 1). "
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    Experimental Neurology 08/2014; 258:5–16. DOI:10.1016/j.expneurol.2014.01.001 · 4.70 Impact Factor
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    • "van Oosten-Hawle and Morimoto 1538 GENES & DEVELOPMENT Cold Spring Harbor Laboratory Press on July 17, 2014 -Published by Downloaded from et al. 2000; Vabulas et al. 2001 "
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    • "Following signal binding, TLRs activate signaling components to initiate different types of immune biological responses. For example, TLR1-TLR2, TLR2-TLR6, and TLR5 induce mainly inflammatory cytokines, whereas TLR3 and TLR4 induce both type I interferon (IFN-I) and inflammatory cytokine Endogenous ligands Hsp60 ( Vabulas et al., 2001 ) Hsp70 ( Vabulas et al., 2002a ) Gp96 ( Vabulas et al., 2002b ) HSPB8 ( Roelofs et al., 2006 ) α -Crystalline ( Roelofs et al., 2006 ) Fibronectin (extra domain A) Hyaluronic acid ( Termeer et al., 2002 ; Jiang et al., 2005 ) Heparan sulfate ( Johnson et al., 2002 ) Fibrinogen ( Smiley et al., 2001 ) Surfactant-protein A ( Guillot et al., 2002 ) HMGB1 protein ( Park et al., 2004 ) β -defensin ( Biragyn et al., 2002 ) "
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