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 un derstand the proinflammatory nature of HSP, we analyzed signaling induced b y human and chlamydial HSP60. We show that both HSP60s activate the stress- activated protein kinases p38 and JNK1/2, the mitogen-activated protein kin ases ERK1/2, and the I-kappaB kinase (IKK). Activation of JNK and IKK proce eds via the Toll/IL-1 receptor signaling pathway involving MyD88 and TRAF6. Human fibroblasts transfected with TLR2 or TLR4 plus MD-2 gain responsiven ess to HSP60, while TLR2- or TLR4-defective cells display impaired response s. Initiation of signaling requires endocytosis of HSP60 that is effectivel y inhibited by serum component(s). The results revealed that adjuvanticity of HSP60 operates similar to that of classical pathogen-derived ligands.