Initiation of the Immune Response by Extracellular Hsp72: Chaperokine Activity of Hsp72

Abstract

Heat shock proteins exert their beneficial effects via basically two modes of action depending on their relative location within the host. Intracellular heat shock proteins found within cells serve a cytoprotective role by chaperoning naïve, misfolded and/or denatured proteins in response to stressful stimuli by a process known as the stress response. However, stressful stimuli also induce the release of intracellular heat shock proteins into the extracellular milieu and circulation. The extracellular heat shock protein proteins serve a cytostimulatory role by initiating immune responses designed to fend off microbial infection and destroy neoplastic transformed cells. This review will briefly cover recent advances into elucidating the mechanism(s) by which stress induces the release of heat shock proteins into the circulation, how it initiates immune responses and suggest the possible biological significance of circulating Hsp to the host.

Increased heat shock protein 70 levels in induced sputum and plasma correlate with severity of asthma patients

“…HSP70 displays a wide range of immunological effects in addition to its cytokine effects, and it can be considered an alarm that alerts our defense system of an impending danger. To better describe the unique function as both chaperone and cytokine, extracellular HSP70 (eHSP70) was named as chaperokine by Asea (2003Asea ( , 2005. eHSP70 can induce the antigen presenting cells (APC) maturation by augmenting the surface expression of CD40, CD83, CD86, and MHC class II molecules on APC and migration of APC (Asea 2005;Asea et al 2002;Srivastava 2002); on the other hand, after exposure of APC to exogenous eHSP70, there is significant release of cytokines including TNF-α, IL-1β, IL-6, and IL-12 (Srivastava 2002), and chemokines including MIP-1, MCP-1, and RANTES.…”

“…To better describe the unique function as both chaperone and cytokine, extracellular HSP70 (eHSP70) was named as chaperokine by Asea (2003Asea ( , 2005. eHSP70 can induce the antigen presenting cells (APC) maturation by augmenting the surface expression of CD40, CD83, CD86, and MHC class II molecules on APC and migration of APC (Asea 2005;Asea et al 2002;Srivastava 2002); on the other hand, after exposure of APC to exogenous eHSP70, there is significant release of cytokines including TNF-α, IL-1β, IL-6, and IL-12 (Srivastava 2002), and chemokines including MIP-1, MCP-1, and RANTES. In addition, eHSP70 has been shown to stimulate monocytes and macrophages to produce pro-inflammatory cytokines such as TNF-, IL-6, and IL-12p40 (Rico et al 1999) and to stimulate the proliferation of T cell and proliferation on B cell populations (Rico et al 1999(Rico et al , 2002.…”

Heat Shock Protein 70, Released from Heat-Stressed Tumor Cells, Initiates Antitumor Immunity by Inducing Tumor Cell Chemokine Production and Activating Dendritic Cells via TLR4 Pathway

“…However, HSP can also serve as cytokines that can stimulate dendritic cells (DC) and macrophages to produce proinflammatory cytokines and chemokines (1)(2)(3)(4)(5). More importantly, HSP derived from tumor cells are capable of chaperoning tumor Ags to DC and then cross-presenting the Ags to T cells (6).…”

“…HSP70 proteins, including the constitutively expressed cognate HSP70 (HSC70 or HSP73), the stress-inducible HSP70 (HSP70i or HSP72), and the mitochondrial HSP70 (HSP75), constitute the most conserved class of all HSP. Previous reports have shown that HSP can be released from various cells via passive (e.g., HSP released during cell injury conditions, such as surgery, excessive exercise, and necrosis) and active (e.g., translocation of HSP to plasma membrane and subsequent secretion) pathways (3)(4)(5). However, the roles of HSP70 proteins released from tumor cells in the induction of antitumor immunity and the underlying mechanisms have not been fully elucidated.…”

Therapeutic implications of autoimmune vitiligo T cells

“…It appears that melanocytes from vitiligo patients will respond differently to stress: we have demonstrated that vitiligo melanocytes will release more HSP70 in response to model stressor compound 4-TBP [18]. Stress proteins can function as peptide chaperones and are capable of activating dendritic cells [19,20]. In fact, stress protein/ tumor antigen fusion proteins are currently in clinical trials for the treatment of human tumors, including melanoma.…”