Inhibitor of apoptosis proteins, NAIP, cIAP1 and cIAP2 expression during macrophage differentiation and M1/M2 polarization

Morón-Calvente, Virginia; Romero-Pinedo, Salvador; Toribio-Castelló, Sofía; Plaza‐Díaz, Julio; Abadía-Molina, Ana Clara; Rojas-Barros, Domingo I.; Beug, Shawn T.; LaCasse, Eric C.; MacKenzie, Alex; Korneluk, Robert G.; Abadía-Molina, Francisco

doi:10.1371/journal.pone.0193643

Cited by 31 publications

(24 citation statements)

References 76 publications

(81 reference statements)

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“…The impact of LCL/LBH exposure on proteins involved in the canonical NF-κB pathway was examined. Exposure (16 or 24 hr) of U266 or MM.1S to LCL (± LBH) markedly downregulated cIAP1 as previously described in multiple other cell types [19][20][21] but had a more modest effect on cIAP2 (Figure 2A and 2B, upper panels). Co-treatment also sharply induced γH2A.X, an indicator of DNA damage known to be induced by Smac-mimetics, 22 in both MM cell lines (Figure 2A and 2B, upper panels).…”

Section: The Combination Of Lcl161 and Lbh589 Down-regulates Ciap1 Induces γH2ax But Does Not Inactivate The Canonical Nf-b Pathway In MMsupporting

confidence: 79%

IAP and HDAC inhibitors interact synergistically in myeloma cells through noncanonical NF-κB– and caspase-8–dependent mechanisms

Zhou¹,

Meads

Dai

et al. 2021

Blood Advances

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Interactions between the IAP antagonist LCL161 and the histone deacetylase inhibitor (HDACI) panobinostat (LBH589) were examined in human multiple myeloma (MM) cells. LCL161 and panobinostat interacted synergistically to induce apoptosis in diverse MM cell lines including those resistant to bortezomib (PS-R). Similar interactions were observed with other HDACIs (MS-275) or IAP antagonists (birinapant). These events were associated with down-regulation of the non-canonical (but not the canonical) NF-κB pathway and activation of the extrinsic, caspase-8- related apoptotic cascade. Co-exposure of MM cells to LCL161/LBH589 induced TRAF3 up-regulation, TRAF2 and NIK down-regulation, diminished expression of BCL-XL and induction of γH2A.X. Ectopic expression of TRAF2, NIK, or BCL-XL, or shRNA TRAF3 knock-down significantly reduced LCL161/LBH589 lethality, as did ectopic expression of dominant-negative FADD. Stromal/microenvironmental factors failed to diminish LCL161/LBH589-induced cell death. The LCL161/LBH589 regimen significantly increased cell killing in primary CD138+ cells (N = 31) and was particularly effective in diminishing the primitive progenitor cell-enriched CD138-/19+/20+/27+ population (N = 23), but was non-toxic to normal CD34+ cells. Finally, combined LCL161/LBH589 treatment significantly increased survival compared to single-agent treatment in an immunocompetent 5TGM1 murine MM model. Together, these findings argue that LCL161 interacts synergistically with LBH589 in MM cells through a process involving inactivation of the non-canonical NF-κB and activation of the extrinsic apoptotic pathways, up-regulation of TRAF3, and TRAF2/BCL-XL down-regulation. Notably, this regimen overcomes various forms of resistance, is active against primary MM cells, and displays significant in vivo activity. This strategy warrants further consideration in MM.

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Section: The Combination Of Lcl161 and Lbh589 Down-regulates Ciap1 Induces γH2ax But Does Not Inactivate The Canonical Nf-b Pathway In MMsupporting

confidence: 79%

IAP and HDAC inhibitors interact synergistically in myeloma cells through noncanonical NF-κB– and caspase-8–dependent mechanisms

Zhou¹,

Meads

Dai

et al. 2021

Blood Advances

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“…NLR family apoptosis inhibitory protein (NAIP) is highly expressed in M2 macrophages, and cellular IAP 1 (cIAP1) and cIAP2 show opposite expression patterns in M1/M2 polarized macrophages with cIAP1 expressed in M2 and cIAP2 preferentially expressed in M1. Interestingly, IAP antagonists can induce the upregulation of NAIP in M2, downregulation of cIAP1 expression in M1 and M2, and high expression of cIAP2 in M1 macrophages ( 38 ).…”

Section: Crosstalk Of Apoptosis and Polarization Of Kcs In I/rmentioning

confidence: 99%

Effect of Hepatic Macrophage Polarization and Apoptosis on Liver Ischemia and Reperfusion Injury During Liver Transplantation

Mao

et al. 2020

Front. Immunol.

107

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Ischemia-reperfusion (I/R) injury is injury caused by a limited blood supply and subsequent blood supply recovery during liver transplantation. Serious ischemia-reperfusion injury is the main cause of transplant failure. Hepatic I/R is characterized by tissue hypoxia due to a limited blood supply and reperfusion inducing oxidative stress and an immune response. Studies have confirmed that Kupffer cells (KCs), resident macrophages in the liver, play a key role in aseptic inflammation induced by I/R. In liver macrophage polarization, M1 macrophages activated by interferon-γ (IFN-γ) and lipopolysaccharide (LPS) exert a pro-inflammatory effect and release a variety of inflammatory cytokines. M2 macrophages activated by IL-4 have an anti-inflammatory response. M1-type KCs are the dominant players in I/R as they secrete various pro-inflammatory cytokines that exacerbate the injury and recruit other types of immune cells via the circulation. In contrast, M2-type KCs can ameliorate I/R through unregulated anti-inflammatory factors. A new notion has been proposed that KC apoptosis may influence I/R in yet another manner as well. Management of KCs is expected to help improve I/R. This review summarizes the effects of hepatic macrophage polarization and apoptosis on liver I/R.

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“…Macrophages have a highly plastic phenotype depending on the immune microenvironment. The extremes of this phenotypic spectrum include classically activated macrophages (M1 phenotype, pro-inflammatory defensive role) and alternative activated macrophages (M2 phenotype, anti-inflammatory and tissue-repair roles) [ 14 ]. Accumulated evidence suggests that an imbalance of M1/M2 is associated with the process of inflammation in many diseases, such as chronic hyperinsulinemia [ 15 ], diabetic nephropathy [ 16 ] and radiation-induced lung fibrosis [ 17 ].…”

Section: Introductionmentioning

confidence: 99%

Cannabinoid 2 receptor attenuates inflammation during skin wound healing by inhibiting M1 macrophages rather than activating M2 macrophages

Ren

Wang

et al. 2018

J Inflamm

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BackgroundThe anti-inflammatory properties of the cannabinoid 2 receptor (CB2R) in injury and inflammatory diseases have been widely substantiated. Specifically, the anti-inflammatory effect of CB2R may be achieved by regulating macrophage polarisation. Several research findings suggested that the activation of CB2R could attenuate inflammation by reducing pro-inflammatory M1 macrophage polarisation and promoting anti-inflammatory M2 polarisation. However, considering CB2R inhibits fibrosis and M2 promotes fibrosis, that the activation of CB2R may lead to an increase in M2 macrophages seems contradictory. Therefore, we hypothesised that the activation of CB2R to attenuate inflammation is not achieved by up-regulating M2 macrophages.MethodsWe established an incised wound model using mouse skin and used this to evaluate the effect of CB2R agonists (JWH133 or GP1a) and an antagonist (AM630) on wound healing. At various post-injury intervals, we used western blot analysis, immunofluorescence staining, enzyme-linked immunosorbent assay and quantitative reverse transcription polymerase chain reaction assays to determine CB2R protein expression, M1/M2 macrophage infiltration, and the protein and gene expression of M1/M2-associated markers and cytokines in skin lesions.ResultsActivation of CB2R significantly reduced M1 macrophage infiltration and slightly increased M2 macrophage infiltration. Similarly, gene expression and protein levels of M1-associated markers and cytokines (interleukin [IL]-6, IL-12, CD86 and inducible nitric oxide synthase) were significantly down-regulated after CB2R agonist administration; in contrast, markers and cytokines were increased in the CB2R antagonist–treated group. Conversely, the administration of agonists slightly increased gene expression and protein levels of M2-associated markers and cytokines (IL-4, IL-10, CD206 and arginase-1 [Arg-1]); however, a statistical significance at most time points post-injury was not noted.ConclusionIn summary, our findings suggested that during incised skin wound healing in mice, increased levels of CB2R may affect inflammation by regulating M1 rather than M2 macrophage subtype polarisation. These results offer a novel understanding of the molecular mechanisms involved in the inhibition of inflammation by CBR2 that may lead to new treatments for cutaneous inflammation.

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Inhibitor of apoptosis proteins, NAIP, cIAP1 and cIAP2 expression during macrophage differentiation and M1/M2 polarization

Cited by 31 publications

References 76 publications

IAP and HDAC inhibitors interact synergistically in myeloma cells through noncanonical NF-κB– and caspase-8–dependent mechanisms

IAP and HDAC inhibitors interact synergistically in myeloma cells through noncanonical NF-κB– and caspase-8–dependent mechanisms

Effect of Hepatic Macrophage Polarization and Apoptosis on Liver Ischemia and Reperfusion Injury During Liver Transplantation

Cannabinoid 2 receptor attenuates inflammation during skin wound healing by inhibiting M1 macrophages rather than activating M2 macrophages

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