After this Hsp10 treatment protocol, the proliferation of T cells within the mixed lymphocyte cultures was not significantly different between Hsptreated and control animals data not shown. Neither T cell IL-4 secretion Fig. T cell IL secretion was slightly but significantly elevated Fig. These data indicate that Hsp10 can enhance IL production in response to mixed lymphocyte culture stimulation and suggest that the Hspenhanced IL production seen above may arise in part from T cell-derived IL To illustrate that tolerance induction was not operating in this system, PBMC were pretreated with a range of LPS concentrations, and 1 h later they were stimulated with 0.
IL-6 is another well known inflammatory cytokine induced by LPS An average No significant reduction in IL-6 secretion was observed when 0. LPS pretreatment for 1 h did not inhibit IL-6 secretion stimulated by a second LPS treatment, again illustrating that tolerance induction was not operating in this system Fig. The Hsp10 treatment provided an average These data are consistent with the tissue culture experiments and illustrate the in vivo efficacy of Hsp10 in reducing pro-inflammatory mediators and increasing IL production after challenge with LPS.
Hsp10 activity in murine inflammatory models. After 1. Error bars represent S. B , pretransplant treatment with Hsp10 delayed GVHD mortality and reduced clinical severity of acute disease. Kaplan-Meier survival curves and clinical scores are shown for the three groups, and the allogeneic groups treated with and without Hsp10 are compared by Log Rank Statistic and non-parametric t test, respectively. Clinical scores were only significantly different on day 7. These cytokines and the allo-reactive T cells then contribute to increasing gastrointestinal damage and LPS leakage.
The effect of Hsp10 administration during the peri-transplant period on GVHD was, therefore, investigated. Hsp10 treatment of transplant donors and recipient animals before transplant significantly delayed GVHD mortality Fig. In addition, the severity of GVHD as determined by the clinical score was also significantly reduced on day 7 after the bone marrow transplantation Fig. Treatment of animals with Hsp10 post-transplant failed in isolation to ameliorate significantly GVHD data not shown.
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The anti-Hsp60 antibody by itself mediated a similar level of inhibition of LPS signaling to that seen for Hsp10 treatment Fig. However, when added together there was no additive inhibitory effect the lack of detectable LUC activity when cells were incubated with either antisera alone illustrated that endotoxin contamination of the antibodies was below the level of detection; see Fig. Hsp10 activity was blocked by anti-Hsp60 serum. LPS was then added, and luciferase activity was measured 2 h later. In addition to its critical role in protein folding within the mitochondria, Hsp10 appears to have an extracellular role in the modulation of specific inflammatory processes.
Heat Shock Proteins: Conditional Mediators of Inflammation in Tumor Immunity
We were unable to confirm previous reports 40 , 41 that anti-Hsp10 antibodies reduced the growth of tumor cells in vitro or in vivo , nor were we able to demonstrate that Hsp10 is a growth factor for tumor cells. Given that E. How Hsp10 mediates its inhibitory activity is unclear, although it appears to effect inhibition very rapidly, within 30 min Fig.
This might implicate inhibition of early signaling events or activation of rapid negative feedback mechanisms such as phosphoinositide 3-kinase However, we have been unable to prevent Hsp10 activity with the specific phosphoinositide 3-kinase inhibitor wortmannin data not shown , suggesting this pathway is not involved in the Hsp10 mechanism of action. The reported association of extracellular Hsp60 with TLR4 signaling 13 and the known interaction between Hsp10 and Hsp60 in the mitochondria suggested that Hsp10 might inhibit LPS-induced TLR4 signaling by interacting with Hsp60 in the extracellular milieu.
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This notion is supported by our finding that Hsp10 activity is blocked and mimicked by anti-Hsp60 antibodies Fig. Although Hsp60 was reported to stimulate TLR2 and TLR4 signaling, recent reports 22 , 67 and our own studies data not shown indicate that such activity is likely due to LPS contamination of Hsp60 preparations.
Nevertheless, in agreement with previous reports 24 , 25 , anti-Hsp60 antibodies were able to inhibit LPS-mediated signaling Fig. A potentially similar role in the augmentation of inflammatory responses has been proposed for Hsp70 and Hsp90 21 , 69 — Hsp60 is also reported to contribute to TLR2 signaling 19 , 72 , and we have recently shown that Hsp10 can also inhibit signaling by a TLR2 agonist, whereas Hsp10 was ineffective in inhibiting TLR9 signaling data not shown.
This line of reasoning might lead one to speculate that the physiological role of circulating Hsp10 during early pregnancy 38 may be to remove the Hsp60 danger signal 15 that has arisen from pregnancy 73 , 74 rather than from pathogen-induced tissue damage. We are currently in the process of seeking formal proof of Hsp10 binding to extracellular Hsp60, as it remains possible that Hsp10 binds to an alternative receptor 75 and that Hsp10 and anti-Hsp60 exert similar suppressive but non-additive effects on TLR4 signaling Fig.
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However, such removal may not always be desirable Multiple sclerosis has been suggested as a possible therapeutic target for Hsp10 since Hsp10 is reported to reduce clinical signs and delay onset of disease in a murine model of multiple sclerosis experimental autoimmune encephalomyelitis Section solely to indicate this fact. You'll be in good company. Journal of Lipid Research. Previous Section Next Section.
Previous Section. Fiaux, J. CrossRef Medline Google Scholar. Meyer, A. Xu, Z. Belles, C. Feng, H. Shin, B. Barazi, H. Kaur, I. Soltys, B. Laad, A. Cancer 80 , — Xu, Q. Lewthwaite, J. Johnson, G. Flohe, S. Wallin, R. Beg, A. Kligman, I. Ueki, K. Zanin-Zhorov, A.
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Cell Biol. Cavanagh, A. Quinn, K. Sweet, M. Mateo, L. Ryan, M. Brinker, A. Linn, M. Methods 52 , 51 — Skehan, P. Cancer Inst. Anraku, I. MacDonald, K. Morse, H. Hill, G. Cooke, K. Yamamoto, A. Gearing, A.
West, M. Fujihara, M. Berlato, C. Suhrbier, A. Granowitz, E. Lynn, M. Kanda, T. Heart J. Apoptotic cells release several chemoattractive factors, including nucleotides, lipids and chemokines, which may attract DCs. Changes in surface molecules on apoptotic cells, for example, expression of calreticulin or HSP and , allow recognition and engulfment of apoptotic bodies Green et al, ; Zitvogel et al, Although apoptotic cells have been suggested to fail to induce DC maturation and to be associated with induction of immunological tolerance, this also appears to depend on the pre-apoptotic conditioning, for example, stress, of the cells together with the sequence of the events rather than solely on apoptotic vs necrotic cell death.
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Science : — Br J Cancer : — Lancet Oncol 8 : — Tisch R Immunogenic versus tolerogenic dendritic cells: a matter of maturation. Int Rev Immunol 29 : — Immunol Rev : — Brain Pathol 19 : — Cell : — Download references. Correspondence to N Etminan. From twelve months after its original publication, this work is licensed under the Creative Commons Attribution-NonCommercial-Share Alike 3.
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Advanced search. Skip to main content. Abstract Background: T-cell responses contribute to the anti-tumoural effect of photodynamic therapy PDT. Main Photodynamic therapy PDT is a promising approach in the treatment of various tumours Dolmans et al, Generation of DCs Buffy coats were obtained from healthy individuals after informed consent. Migration assay To assess migration of immature DCs towards spheroids, a transwell assay was used.
Figure 1 Chemoattractive activity of glioma spheroids for immature DCs. Full size image. Figure 2 Uptake of tumour material from glioma spheroids by immature DCs. Figure 3 Dendritic cell maturation-inducing activity of glioma spheroids. Figure 4 Allostimulatory activity of DCs matured in the presence of glioma spheroids. Discussion There is clear evidence for an immunological component in the anti-tumoural effect of PDT from extracranial tumours Castano et al, Change history 29 March Rights and permissions From twelve months after its original publication, this work is licensed under the Creative Commons Attribution-NonCommercial-Share Alike 3.