Differential Role of Rapamycin and Torin/KU63794 in Inflammatory Response of 264.7 RAW Macrophages Stimulated by CA-MRSA

Shappley, Rebekah; Spentzas, Thomas

doi:10.1155/2014/560790

Cited by 6 publications

(4 citation statements)

References 32 publications

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“…The mTORC links with other proteins and serves as a core component of two distinct protein complexes, mTORC-1 and mTORC-2, which regulate different cellular processes (34). The role of mTORC complexes was investigated by using the chemical inhibitors rapamycin, which inhibits mTORC-1, and torin, which inhibits both complexes (35,36). Because ribosomal p70S6 kinase is a downstream target of the mTORC-1 complex (34), we also investigated the role of p70S6K in the SM-induced cell death.…”

Section: Sm-induced Cell Death During Differentiation Into M1 Macroph...mentioning

confidence: 99%

Selective Induction of Cell Death in Human M1 Macrophages by Smac Mimetics Is Mediated by cIAP-2 and RIPK-1/3 through the Activation of mTORC

Ali

Dong

Gajanayaka

et al. 2021

The Journal of Immunology

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Inflammatory macrophages have been implicated in many diseases, including rheumatoid arthritis and inflammatory bowel disease. Therefore, targeting macrophage function and activation may represent a potential strategy to treat macrophageassociated diseases. We have previously shown that IFN-ginduced differentiation of human M0 macrophages toward proinflammatory M1 state rendered them highly susceptible to the cytocidal effects of second mitochondria-derived activator of caspases mimetics (SMs), antagonist of the inhibitors of apoptosis proteins (IAPs), whereas M0 and anti-inflammatory M2c macrophages were resistant. In this study, we investigated the mechanism governing SM-induced cell death during differentiation into M1 macrophages and in polarized M1 macrophages. IFN-g stimulation conferred on M0 macrophages the sensitivity to SMinduced cell death through the Jak/STAT, IFN regulatory factor-1, and mammalian target of rapamycin complex-1 (mTORC-1)/ ribosomal protein S6 kinase pathways. Interestingly, mTORC-1 regulated SM-induced cell death independent of M1 differentiation. In contrast, SM-induced cell death in polarized M1 macrophages is regulated by the mTORC-2 pathway. Moreover, SM-induced cell death is regulated by cellular IAP (cIAP)-2, receptor-interacting protein kinase (RIPK)-1, and RIPK-3 degradation through mTORC activation during differentiation into M1 macrophages and in polarized M1 macrophages. In contrast to cancer cell lines, SM-induced cell death in M1 macrophages is independent of endogenously produced TNF-a, as well as the NF-kB pathway. Collectively, selective induction of cell death in human M1 macrophages by SMs may be mediated by cIAP-2, RIPK-1, and RIPK-3 degradation through mTORC activation. Moreover, blocking cIAP-1/2, mTORC, or IFN regulatory factor-1 may represent a promising therapeutic strategy to control M1-associated diseases.

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Section: Sm-induced Cell Death During Differentiation Into M1 Macroph...mentioning

confidence: 99%

Selective Induction of Cell Death in Human M1 Macrophages by Smac Mimetics Is Mediated by cIAP-2 and RIPK-1/3 through the Activation of mTORC

Ali

Dong

Gajanayaka

et al. 2021

The Journal of Immunology

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“…After 3 d of differentiation in response to the biomaterial, the medium was removed and replaced with medium containing 1 or 10 ng ml −1 rapamycin (R&D Systems), or 10 −8 or 10 −7 M dexamethasone (Sigma-Aldrich), or 0.5 or 5 μM pravastatin (Sigma-Aldrich), or 0.1 or 1 μM celecoxib (Sigma-Aldrich). Concentrations were chosen based on literature [26,28,38,39] and previous work in whichmacrophages cultured in monolayers were treated with these medications [23]. Dimethyl sulfoxide (DMSO) was used as avehicle for dexamethasone and rapamycin and the final DMSO concentration in the cultures was <0.01%.…”

Section: Modulation Of Macrophages Adhering To Biomaterialsmentioning

confidence: 99%

In vitro modulation of the behavior of adhering macrophages by medications is biomaterial-dependent

et al. 2017

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After implantation of a biomaterial, an inflammatory response involving macrophages is induced. The behavior of macrophages depends on their phenotype, and by directing macrophage polarization unwanted effects may be avoided. In this study, the possibility to modulate the behavior of macrophages activated by biomaterials was assessed in an in vitro model. Primary human monocytes were seeded on polyethylene terephthalate, polypropylene and polylactic acid yarns, and treated with medications frequently used by patients: rapamycin, dexamethasone, celecoxib or pravastatin. Modulation of the adhering macrophages with rapamycin resulted in a generally pro-inflammatory effect. Dexamethasone caused an overall anti-inflammatory effect on the macrophages cultured on either material, while celecoxib only affected macrophages adhering to polyethylene terephthalate and polylactic acid. Pravastatin increased the pro-inflammatory genes of macrophages cultured on polypropylene and polylactic acid. Pairwise comparison revealed that macrophages adhering to polylactic acid seemed to be more susceptible to phenotype modulation than when adhering to polypropylene or polyethylene terephthalate. The data show that macrophages activated by the biomaterials can be modulated, yet the degree of the modulatory capacity depends on the type of material. Combined, this model provides insights into the possibility of using a medication in combination with a biomaterial to direct macrophage behavior and thereby possibly avoid unwanted effects after implantation.

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“…Rapamycin was found to exhibit a significant induction-suppression biphasic response, whereas mTORC1/2 inhibitors did not exhibit induction and cytokine production was suppressed 50%-60%. 131 Similarly, another recent study has shown that mTORC1/2 inhibition can inhibit inflammatory activity in lipopolysaccharide-activated RAW 264.7 cells. 132 The differential effect of different mTOR inhibitors on inflammatory response could indirectly have an effect on tumor response.…”

mentioning

confidence: 92%

Recent insights into the pathophysiology of mTOR pathway dysregulation

Gitto¹,

Altomare

2015

RRB

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Mechanistic target of rapamycin (mTOR) dysregulation is present in a variety of human pathologies including neurological disease, cancer, diabetes, and cardiac disease. Hyperactivation leads to increased protein synthesis and cell growth, which are essential for growth, development, and cancer. Inhibition of mTOR results in induction of autophagy, a cell survival mechanism thought to be deficient in neurodegeneration. Counteracting the balance of mTOR signaling with target specific inhibitors is of interest in pathological conditions where mTOR signaling is upregulated. The US Food and Drug Administration (FDA) has approved the use of rapamycin for treatment of renal cell, pancreatic neuroendocrine, and hormone positive breast cancer. Many clinical trials are underway to determine the efficacy of mTOR inhibitors in other pathologies as monotherapies or combinational therapies with chemotherapeutics, tyrosine kinase inhibitors, molecular targeted therapies, and vascular endothelial growth factor (VEGF) inhibitors. Collectively, this review is an overview of the current practices and outcomes of pharmaceutically targeting this highly studied mediator of normal and aberrant cell function.

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Differential Role of Rapamycin and Torin/KU63794 in Inflammatory Response of 264.7 RAW Macrophages Stimulated by CA-MRSA

Cited by 6 publications

References 32 publications

Selective Induction of Cell Death in Human M1 Macrophages by Smac Mimetics Is Mediated by cIAP-2 and RIPK-1/3 through the Activation of mTORC

Selective Induction of Cell Death in Human M1 Macrophages by Smac Mimetics Is Mediated by cIAP-2 and RIPK-1/3 through the Activation of mTORC

In vitro modulation of the behavior of adhering macrophages by medications is biomaterial-dependent

Recent insights into the pathophysiology of mTOR pathway dysregulation

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