Lipid A-Mediated Tolerance and Cancer Therapy

Rockwell, Cheryl E.; Morrison, David C.; Qureshi, Nilofer

doi:10.1007/978-1-4419-1603-7_8

Cited by 11 publications

(14 citation statements)

References 134 publications

(99 reference statements)

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“…This topic on tolerance mechanisms has been recently reviewed by others and us (5, 27-31). Our model (Figure 7) is consistent with most previous mechanisms of tolerance, because transcription/degradation of all cytokines and signaling proteins mentioned above is proteasome-dependent (12).…”

Section: Discussionmentioning

confidence: 97%

“…Similarly, we have shown that phosphorylation of ERK-1, JNK-1 and p38 (MAPK) is also proteasome dependent (10). Our data suggest that initial interaction of LPS with host macrophages induces the post-acidic activity in RAW 264.7 cells, and then chymotrypsin-like, and trypsin-like activities in cells, initiating a process of proteasome-mediated degradation of signaling mediators such as TLR4, IRAK-1, IRAKM, phosphorylated interferon regulatory factor 3 (P-IRF3), TNF receptor associated factor (TRAF6), IκB-α, β, p105 degradation (responsible for biosynthesis of p50 subunits), and MAPK because of changes in proteasomal activities, proteasome subunits (priming, LMP mode), ubiquitination/deubiquitination and expression of proinflammatory cytokines (5, 11), This also leads to a net increase in ubiquitinated proteins and increased activation of transcription factors, such as NF-κB (33), however HIF-1 (34), Keap/NRF2 (35) and PPAR-γ are inhibited following proteasome's activation. In contrast, during tolerance, very low proteasome subunit expression and activity, leads to inhibition in NF-κB activation, but activation of HIF-1, PPAR-γ, and NrF2 transcription activities.…”

Section: Discussionmentioning

confidence: 99%

“…Viability of peritoneal macrophages treated with LPS was determined by a quantitative colorimetric assay with 3-(4, 5)-dimethylthiozol-2, 5-diphenyltetrazolium bromide (MTT) as described previously (11, 12). No cell death was observed during the experiments.…”

Section: Methodsmentioning

confidence: 99%

“…Tolerance, is thought to occur as a compensatory measure to reduce inflammation in the host and has been extensively studied over the past 70 years (3-5). When the initial LPS treatment tranduces a signal in the cell via interaction with membrane CD14, LPS-binding protein (LBP), toll-like receptor 4 (TLR4) and MD2 proteins, it recruits adaptor proteins, that leads to activation of NF-κB, and other transcription factors ultimately resulting in upregulation of gene and protein expression of inflammatory cytokines (6).…”

Section: Introductionmentioning

confidence: 99%

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Of Mice and Men

Silswal

Reis

Qureshi

et al. 2017

Shock

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The molecular basis responsible for tolerance following inflammatory response to LPS is not well-understood. We hypothesized that inflammation/tolerance in monocytes/ macrophages is dependent on the proteases of proteasome. To test our hypothesis, first, we examined the expression of different proteasome subunits in different human and mouse monocytes/macrophages. Secondly, we investigated the effect of proteasome subunits/ proteases on LPS-induced expression of tumor necrosis factor-α (TNF-α) and nitric oxide (NO) during inflammation and tolerance using mouse RAW 264.7 macrophages, THP1 cells, and cluster of differentiation 14 positive (CD14+) human monocytes. We found that RAW 264.7 cells (XYZ), mouse peritoneal resident, thioglycollate-elicited macrophages, primed RAW 264.7 (XYZ, LMP) and human monocytes (LMP) expressed different types of proteasome subunits/activities. Cells containing predominantly either LMP subunits (such as THP-1 and human monocytes), or only X, Y, Z subunits (RAW 264.7 cells not primed) could only induce TNF-α, but not NO, while cells containing all five-six subunits (XYZ, LMP) of the proteasome could induce both mediators in response to LPS. Distinct states of inflammation/tolerance in LPS treated cells, strongly correlated with an upregulation or downregulation of proteasome's subunits (proteases), respectively. Moreover, interferon-γ (IFN-γ) treatment of tolerant cells caused robust induction of proteasome's subunit expression in mouse macrophages and human monocytes, and cells regained their ability to respond to LPS. These studies are vital for understanding function of proteasome's subunits during inflammation/tolerance in mouse and human cells, and for design of therapeutic strategies for all diseases based on inflammation.

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Section: Discussionmentioning

confidence: 97%

Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Of Mice and Men

Silswal

Reis

Qureshi

et al. 2017

Shock

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“…When produced in excess in response to LPS, these proinflammatory mediators can promote the development of systemic inflammation that can progress to a life-threatening condition termed septic shock. Results from our recently completed studies have revealed that macrophage proteasomes play a pivotal role in regulation of LPS-induced signaling and regulation of gene expression and, via this mechanism, are key regulators of macrophage-dependent inflammatory responses [1–11]. The 26S proteasomes are multi-protein protease complexes which serve a key function in mammalian cells by degrading ubiquitinated proteins.…”

Section: 1 Introductionmentioning

confidence: 99%

Proteasome protease mediated regulation of cytokine induction and inflammation

Qureshi

Morrison

Reis

2012

Biochimica et Biophysica Acta (BBA) - Molecular Cell Research

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We have previously demonstrated that the proteasome serves as a central regulator of inflammation and macrophage function. Until recently, proteasomes have generally been considered to play a relatively passive role in regulation of cellular activity, i.e., any ubiquitinated protein was considered to be in discriminatively targeted for degradation by the proteasome. We have demonstrated, however, by using specific proteasome protease inhibitors and knockout mice lacking specific components of immunoproteasomes, that proteasomes (containing X, Y, and Z protease subunits) and immunoproteasomes (containing LMP7, LMP2, and LMP10 protease subunits) have well-defined functions in cytokine induction and inflammation based on their individual protease activities. We have also shown that LPS-TLR mediated signaling in the murine RAW 264.7 macrophage cell line results in the replacement of macrophage immunoproteasomal subunits. Such modifications serve as pivotal regulators of LPS-induced inflammation. Our findings support the relatively novel concept that defects in structure/function of proteasome protease subunits caused by genetic disorders, aging, diet, or drugs may well have the potential to contribute to modulation of proteasome activity. Of particular relevance, we have identified quercetin and resveratrol, significant constituents present in berries and of red wine respectively, as two novel proteasome inhibitors that have been previously implicated as disease-modifying natural products. We posit that natural proteasome inhibitors/activators can potentially be used as therapeutic response modifiers to prevent/treat diseases through pathways involving the ubiquitin-proteasome pathway (UP-pathway), which likely functions as a master regulator involved in control of overall inflammatory responses.

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Small‐Molecule Carbohydrate‐Based Immunostimulants

Marzabadi

Franck

2016

Chemistry A European J

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In this review, we discuss small-molecule, carbohydrate-based immunostimulants that target Toll-like receptor 4 (TLR-4) and cluster of differentiation 1D (CD1d) receptors. The design and use of these molecules in immunotherapy as well as results from their use in clinical trials are described. How these molecules work and their utilization as vaccine adjuvants are also discussed. Future applications and extensions for the use of these analogues as therapeutic agents will be outlined.

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Lipid A-Mediated Tolerance and Cancer Therapy

Cited by 11 publications

References 134 publications

Of Mice and Men

Of Mice and Men

Proteasome protease mediated regulation of cytokine induction and inflammation

Small‐Molecule Carbohydrate‐Based Immunostimulants

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