Trends in Biochemical Sciences
ReviewThe dual immunoregulatory roles of stress proteins
Section snippets
Re-evaluating the immunological properties of extracellular stress proteins
Heat shock proteins (Hsps) and glucose-regulated proteins (grp) [referred to as stress proteins (SPs) in this article] are essential for cytoprotection and protein folding. Although most of the Hsps localize to the cytoplasm, the grps are expressed in the lumen of the endoplasmic reticulum (ER) (Figure 1). Members of these protein families are present in all species and are categorized into several families that are named on the basis of the approximate molecular weight (Mr) of their members
Stress proteins as activators of innate immune responses
Many studies show Hsp60 and Hsp70 have pro-inflammatory properties when interacting with monocytes, macrophages and dendritic cells (DCs). Human Hsp60 induces the secretion of IL-6 from macrophages, as does chlamydial Hsp60 [19]. Human Hsp60 also induces rapid release of tumor necrosis factor-α (TNF-α) and nitric oxide from human macrophages, as well as IL-12 and IL-15 [20]. It has also been reported to upregulate co-stimulatory molecules CD86 and CD40 in a murine macrophage cell line, enhance
Cell-surface receptors for Hsp60 and Hsp70
Hsp60 and Hsp70 have been reported to use several cell-surface receptors, most notably CD14, CD40 and Toll-like-receptors (TLRs) (Figure 2; reviewed in [24]). In the past year it was demonstrated that microbial Hsp60 and Hsp70 also interact with, and induce the expression of, the chemokine receptor CCR5 25, 26.
TLRs were originally shown to recognize various components of invading pathogens and these receptors are expressed on many cell types, including DCs, macrophages and T cells. TLRs contain
The immune-stimulatory effects of mammalian SPs in tumor immunology: cross-presentation of tumor antigens
Although a wealth of evidence has also been derived from studies of the capacity of SPs to induce immunity to viral and model antigens, much of the information regarding the capacity of endogenous or self SPs to induce pro-inflammatory adaptive immune responses arises from numerous convincing studies in which tumor-derived SPs have been used as anti-tumor vaccine preparations. With respect to this application, members of the Hsp70 super-family, such as Hsp70 itself, Hsp110 and gp170, as well as
The anti-inflammatory properties of endogenous or identical SPs
The immune responses induced as a consequence of vaccination strategies might differ quantitatively and qualitatively from those induced following an encounter with SPs derived from pathogenic organisms or an encounter with endogenous (self) SPs. When self-reactive (low affinity) T cells encounter endogenous (self) stress proteins they typically do so via interactions with APCs in the absence of concomitant inflammatory signals. By contrast, when pathogen SP-specific T cells encounter
Concluding remarks
Stress proteins are emerging as powerful immunomodulatory molecules that can have stimulatory and inhibitory effects on immune responses. Although many studies have been performed in this area, the apparently dichotomous immune functionality of SPs is still not fully explained. SP-mediated immunoregulation is a complex issue and difficulties with investigating and understanding the balance between SP-promotion and control of inflammatory responses lie ahead. Currently, SP immunobiologists are
Acknowledgements
Stress protein-related research in the Pockley laboratory has been, and is being, supported by the National Institutes of Health research grant R21HL69726, the Association for International Cancer Research, the British Heart Foundation and Yorkshire Cancer Research, and support in the Calderwood laboratory is from National Institutes of Health research grants R01CA047407 and R01CA094397.
Glossary
- Anergy
- A term describing the lack of ability of immune cells to generate an immune response to foreign antigens.
- Antigen presenting cell (APC)
- An immune cell that displays foreign antigen that is complexed with MHC molecules on its surface, and presents this to T cells (lymphocytes), which express receptors that recognize this complex.
- CD (Cluster of differentiation)
- A protocol used for the identification and study of cell-surface molecules expressed by white blood cells (leukocytes). The CD
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