Inducible Heat Shock Protein 70 Reduces T Cell Responses and Stimulatory Capacity of Monocyte-derived Dendritic Cells

Stocki, Paweł; Wang, Xiao N.; Dickinson, Anne

doi:10.1074/jbc.m111.307579

Cited by 62 publications

(52 citation statements)

References 33 publications

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“…32 It is worth noting that the absence of minute amounts of contaminating endotoxin is mandatory to reveal the inherent suppressive functions of these HSPs, as nicely demonstrated by Stocki. 33,34 This very low level of contamination could account for the maturation effect of recombinant HSP110 on dendritic cells observed by Manjili et al 35 . In our setting, we eliminated this caveat as we used an HSP110 naturally present in the supernatant of CRC cell lines, and when we used purified HSP110, it was produced in a eukaryotic setting with no traces of LPS.…”

Section: E1170264-6mentioning

confidence: 98%

Extracellular HSP110 skews macrophage polarization in colorectal cancer

et al. 2016

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HSP110 is induced by different stresses and, through its anti-apoptotic and chaperoning properties, helps the cells to survive these adverse situations. In colon cancers, HSP110 is abnormally abundant. We have recently showed that colorectal cancer (CRC) patients with microsatellite instability (MSI) had an improved response to chemotherapy because they harbor an HSP110 inactivating mutation (HSP110DE9). In this work, we have used patients' biopsies and human CRC cells grown in vitro and in vivo (xenografts) to demonstrate that (1) HSP110 is secreted by CRC cells and that the amount of this extracellular HSP110 is strongly decreased by the expression of the mutant HSP110DE9, (2) Supernatants from CRC cells overexpressing HSP110 or purified recombinant human HSP110 (LPS-free) affect macrophage differentiation/polarization by favoring a pro-tumor, anti-inflammatory profile, (3) Conversely, inhibition of HSP110 (expression of siRNA, HSP110DE9 or immunodepletion) induced the formation of macrophages with a cytotoxic, pro-inflammatory profile. (4) Finally, this effect of extracellular HSP110 on macrophages seems to implicate TLR4. These results together with the fact that colorectal tumor biopsies with HSP110 high were infiltrated with macrophages with a pro-tumoral profile while those with HSP110 low were infiltrated with macrophages with a cytotoxic profile, suggest that the effect of extracellular HSP110 function on macrophages may also contribute to the poor outcomes associated with HSP110 expression.

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Section: E1170264-6mentioning

confidence: 98%

Extracellular HSP110 skews macrophage polarization in colorectal cancer

et al. 2016

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“…For example, it has been reported as a carrier of antigens to antigen-presenting cells (Lussow et al 1991;Nishikawa et al 2007), as pro-inflammatory mediator (Kono and Rock 2008), or on the contrary, as an anti-inflammatory molecule that inhibits maturation and induces the secretion of IL-10 in DCs (Detanico et al 2004;Motta et al 2007). However, the idea of HSP70 as a pro-inflammatory mediator has been considered controversial since several groups have shown that bacterial products often present in HSP70 protein preparations were responsible for the detected pro-inflammatory phenotype (Bausinger et al 2002;Bendz et al 2008;Stocki et al 2012). Therefore, for the experiments performed here, HSP70 preparation with less than 2.1 EU LPS/mg was used.…”

Section: Discussionmentioning

confidence: 99%

Mycobacterial and mouse HSP70 have immuno-modulatory effects on dendritic cells

Spiering

Zee

Wagenaar

et al. 2013

Cell Stress and Chaperones

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Previously, it has been shown that heat shock protein 70 (HSP70) can prevent inflammatory damage in experimental autoimmune disease models. Various possible underlying working mechanisms have been proposed. One possibility is that HSP70 induces a tolerogenic phenotype in dendritic cells (DCs) as a result of the direct interaction of the antigen with the DC. Tolerogenic DCs can induce antigen-specific regulatory T cells and dampen pathogenic T cell responses. We show that treatment of murine DCs with either mycobacterial (Mt) or mouse HSP70 and pulsed with the disease-inducing antigen induced suppression of proteoglycan-induced arthritis (PGIA), although mouse HSP70-treated DCs could ameliorate PGIA to a greater extent. In addition, while murine DCs treated with Mt-or mouse HSP70 had no significantly altered phenotype as compared to untreated DCs, HSP70-treated DCs pulsed with pOVA (ovalbumin peptide 323-339) induced a significantly increased production of IL-10 in pOVA-specific T cells. IL-10-producing T cells were earlier shown to be involved in Mt HSP70-induced suppression of PGIA. In conclusion, this study indicates that Mt-and mouse HSP70-treated BMDC can suppress PGIA via an IL-10-producing T cell-dependent manner.

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“…Controversy surrounds many HSPs and their proinflammatory roles, and mainly results from endotoxin contamination artefacts which seems to be commonly overlooked due to a dogmatic approach adopted by some of the scientific community. Many reviews were written and argued for or against mammalian HSP70 proinflammatory functions; however the fact remains that in those publications where the striking “danger signal-like” proinflammatory activity of HSP70 was shown, researchers used the endotoxin contaminated recombinant protein provided by Stressgen Biotechnologies [16, 25, 26]. Therefore in this paper we dismiss any data from studies where HSP70 endotoxin contamination was neglected and we will concentrate only on reports where HSP70 purified from a nonbacterial origin was used or studies where endotoxin contamination was stringently controlled.…”

Section: Tantrum About Proinflammatory Functions Of Hsp70mentioning

confidence: 99%

The Immunosuppressive Activity of Heat Shock Protein 70

Stocki

Dickinson

2012

Autoimmune Diseases

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Heat shock protein 70 (HSP70) has previously been described as a potent antitumour vaccine. The mechanism relied on the ability of tumour derived HSP70 to associate with antigenic peptides, which, when cross presented, elicited a T cell mediated antitumour response. Subsequently, HSP70 was incorrectly described as a potent adjuvant of innate immunity, and although mistakes in the experimental approaches were exposed and associated with endotoxin contamination in the recombinant HSP70 specimen, questions still remain regarding this matter. Here we review only publications that have cautiously addressed the endotoxin contamination problem in HSP70 in order to reveal the real immunological function of the protein. Accordingly, “endotoxin free” HSP70 stimulates macrophages and delivers antigenic peptides to APCs, which effectively prime T cells mediating an antitumour reaction. Conversely, HSP70 has potent anti-inflammatory functions as follows: regulating T cell responses, reducing stimulatory capacity of DCs, and inducing development of immunosuppressive regulatory T cells. These activities were further associated with the immune evasive mechanism of tumours and implicated in the modulation of immune reactivity in autoimmune diseases and transplant-related clinical conditions. Consequently, the role of HSP70 in immune regulation is newly emerging and contrary to what was previously anticipated.

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Inducible Heat Shock Protein 70 Reduces T Cell Responses and Stimulatory Capacity of Monocyte-derived Dendritic Cells

Cited by 62 publications

References 33 publications

Extracellular HSP110 skews macrophage polarization in colorectal cancer

Extracellular HSP110 skews macrophage polarization in colorectal cancer

Mycobacterial and mouse HSP70 have immuno-modulatory effects on dendritic cells

The Immunosuppressive Activity of Heat Shock Protein 70

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