Releasing signals, secretory pathways, and immune function of endogenous extracellular heat shock protein 72

Johnson, John D.; Fleshner, Monika

doi:10.1189/jlb.0905523

Cited by 226 publications

(206 citation statements)

References 124 publications

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“…A new role has emerged for large HSP as endogenous danger signals which augment the induction of innate and adaptive immunity through interaction with TLR [6,7,9]. In contrast, our data suggest a novel role for HSP-27 as an MO anti-danger signal down-modulating innate and adaptive immunity similar to the role suggested for CD200 [49].…”

Section: Discussionsupporting

confidence: 45%

“…Since p38 activation is typical of TLR stimulation and some TLR have been suggested as HSP receptors, we investigated whether HSP-27 can modulate p38 activation via effects on TLR signaling [7,48]. Treatment of MO with LPS is known to down-regulate TLR4 expression and induce p38 MAP kinase [23].…”

Section: Hsp-27 Stimulation Involves Tlr4mentioning

confidence: 99%

“…Circulating large and small heat shock proteins (HSP) are implicated as modulating adaptive and innate immunity in a variety of disease and inflammatory pathologies beyond their defined chaperone effects [1][2][3][4][5][6][7][8]. Large HSP are thought to act as endogenous danger signals augmenting inflammatory cytokines by triggering monocyte (MO) Toll-like receptors (TLR) and scavenger receptors independently of LPS contaminants [6,7,[9][10][11].…”

Section: Introductionmentioning

confidence: 99%

“…Large HSP are thought to act as endogenous danger signals augmenting inflammatory cytokines by triggering monocyte (MO) Toll-like receptors (TLR) and scavenger receptors independently of LPS contaminants [6,7,[9][10][11]. In contrast, exogenous HSP-27 (a small HSP) predominantly stimulates MO IL-10 [12].…”

Section: Introductionmentioning

confidence: 99%

“…Similarly, alterations in MU receptor expression distorts their phagocytic and effector functions [16,23]. HSP-27 through its interaction with MO TLR or other receptors may modulate expression of other crucial receptors [2,5,7]. Here we assess exogenous HSP-27 for its potential to redirect MO differentiation, derange DC and/or MU activation, and distort DC or MU interaction potential by altering receptor expression, signal transduction, and/or cytokine production.…”

Section: Introductionmentioning

confidence: 99%

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Exogenous heat shock protein 27 uniquely blocks differentiation of monocytes to dendritic cells

Laudański

Miller-Graziano

2007

Eur J Immunol

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Circulating heat shock protein (HSP)‐27 is associated with tumor progression and increased post‐injury infection. Extracellular HSP‐27 might alter monocyte (MO)‐derived DC and/or MΦ function to mediate immunosuppression. HSP‐27 treatment inhibited expression of CD1a and CD1b/c, antigen uptake, and allogeneic T cell induction (MLR) by IL‐4 + GM‐CSF‐differentiated human DC while increasing some MΦ characteristics (↑CD14, ↑CD16, ↑CD163). MO cytokine receptor profiles elicited by 24‐h exogenous HSP‐27 treatment remained supportive of immature DC (iDC) emergence (↑IL‐4R, ↓IL‐6R, ↓M‐CSFR). IL‐10, IL‐6, and M‐CSF (which promote MΦ differentiation) were significantly increased in IL‐4 + GM‐CSF + HSP‐27 MO→iDC differentiation cultures. However, HSP‐27 treatment during MO differentiation to DC increased programmed cell death ligand 1 coinhibitor and depressed CD86 costimulator expression in parallel to decreased iDC MLR activity. This suggested that increased MΦ differentiation was not solely responsible for HSP‐27 reduction of differentiating DC activity. HSP‐27 treatment actually depressed the phagocytic capacity of MO differentiated to MΦ by IL‐10 or M‐CSF culture. CD163 (hemoglobin receptor) expression was depressed on M‐CSF + HSP‐27 MO‐derived MΦ. HSP‐27‐mediated inhibition of MO→iDC differentiation was reversed by p38α & β inhibitor (SB202190) addition or TLR4 receptor modulation. HSP‐27 impaired appropriate MO→iDC and MO→MΦ differentiation modulating expression of receptors necessary for their proper functions. This suggests that endogenous HSP‐27 has immunoregulatory activities which could contribute to immunopathology.

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Section: Discussionsupporting

confidence: 45%

Section: Hsp-27 Stimulation Involves Tlr4mentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

Exogenous heat shock protein 27 uniquely blocks differentiation of monocytes to dendritic cells

Laudański

Miller-Graziano

2007

Eur J Immunol

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HSP70 expression: does it a novel fatigue signalling factor from immune system to the brain?

Heck

Schöler

Bittencourt

2011

Cell Biochemistry & Function

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Integrative physiology studies have shown that immune system and central nervous system interplay very closely towards behavioural modulation. Since the 70-kDa heat shock proteins (HSP70s), whose heavy expression during exercise is well documented in the skeletal muscle and other tissues, is also extremely well conserved in nature during all evolutionary periods of species, it is conceivable that HSP70s might participate of physiologic responses such as fatigue induced by some types of physical exercise. In this way, increased circulating levels of extracellular HSP70 (eHSP70) could be envisaged as an immunomodulatory mechanism induced by exercise, besides other chemical messengers (e.g. cytokines) released during an exercise effort, that are able to binding a number of receptors in neural cells. Studies from this laboratory led us to believe that increased levels of eHSP70 in the plasma during exercise and the huge release of eHSP70 from lymphocytes during high-load exercise bouts may participate in the fatigue sensation, also acting as a danger signal from the immune system.

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The multicellular signalling network of ovarian cancer metastases

Sommerfeld¹,

Finkernagel²,

Jansen³

et al. 2021

Clinical & Translational Med

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BackgroundTranscoelomic spread is the major route of metastasis of ovarian high‐grade serous carcinoma (HGSC) with the omentum as the major metastatic site. Its unique tumour microenvironment with its large populations of adipocytes, mesothelial cells and immune cells establishes an intercellular signaling network that is instrumental for metastatic growth yet poorly understood.MethodsBased on transcriptomic analysis of tumour cells, tumour‐associated immune and stroma cells we defined intercellular signaling pathways for 284 cytokines and growth factors and their cognate receptors after bioinformatic adjustment for contaminating cell types. The significance of individual components of this network was validated by analysing clinical correlations and potentially pro‐metastatic functions, including tumour cell migration, pro‐inflammatory signal transduction and TAM expansion.ResultsThe data show an unexpected prominent role of host cells, and in particular of omental adipocytes, mesothelial cells and fibroblasts (CAF), in sustaining this signaling network. These cells, rather than tumour cells, are the major source of most cytokines and growth factors in the omental microenvironment (n = 176 vs. n = 13). Many of these factors target tumour cells, are linked to metastasis and are associated with a short survival. Likewise, tumour stroma cells play a major role in extracellular‐matrix‐triggered signaling. We have verified the functional significance of our observations for three exemplary instances. We show that the omental microenvironment (i) stimulates tumour cell migration and adhesion via WNT4 which is highly expressed by CAF; (ii) induces pro‐tumourigenic TAM proliferation in conjunction with high CSF1 expression by omental stroma cells and (iii) triggers pro‐inflammatory signaling, at least in part via a HSP70–NF‐κB pathway.ConclusionsThe intercellular signaling network of omental metastases is majorly dependent on factors secreted by immune and stroma cells to provide an environment that supports ovarian HGSC progression. Clinically relevant pathways within this network represent novel options for therapeutic intervention.

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Releasing signals, secretory pathways, and immune function of endogenous extracellular heat shock protein 72

Cited by 226 publications

References 124 publications

Exogenous heat shock protein 27 uniquely blocks differentiation of monocytes to dendritic cells

Exogenous heat shock protein 27 uniquely blocks differentiation of monocytes to dendritic cells

HSP70 expression: does it a novel fatigue signalling factor from immune system to the brain?

The multicellular signalling network of ovarian cancer metastases

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