Effects of the mTOR inhibitor Rapamycin on Monocyte-Secreted Chemokines

Lin, Hugo You-Hsien; Chang, Kai-Ting; Hung, Chi‐Chih; Kuo, Chang-Hung; Hwang, Shang‐Jyh; Chen, Hung‐Chun; Hung, Chih‐Hsing; Lin, Sheng-Fuu

doi:10.1186/s12865-014-0037-0

Cited by 58 publications

(46 citation statements)

References 45 publications

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“…The inhibition of mTOR markedly ameliorated macrophage infiltrates, tubular injuries and fibrosis, which may work through a suppression of inflammatory chemokines in macrophages. These findings are in agreement with previous reports that LPS could induce an abundant expression of chemokines in macrophages through the activation of mTOR signaling, which could be significantly suppressed by rapamycin [36,37] . It will be challenging to further explore the role of mTOR in macrophage dynamics and its correlation with outcomes of kidney disease.…”

Section: Discussionsupporting

confidence: 83%

Lipopolysaccharide Induces Chronic Kidney Injury and Fibrosis through Activation of mTOR Signaling in Macrophages

et al. 2015

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Background: Septic kidney injury is one of the most common complications in critically ill patients with a high risk of developing chronic kidney disease (CKD). Emerging data indicate that mammalian target of rapamyci (mTOR) signaling plays a major role in septic inflammation by regulating the immune response of macrophage. This study was designed to evaluate the role of mTOR signaling in kidney macrophages during endotoxemia-induced chronic kidney injury and subsequent fibrogenesis. Methods: Male C57BL/6 mice were used for all animal studies (n = 9 for each group). Lipopolysaccharide (LPS) was injected intraperitoneally (1 mg/kg) every 2 days to induce persistent endotoxemia. Rapamycin (1 mg/kg·day) was administered to a subgroup of mice 1 day prior to LPS treatment and continued to termination of the experiment. In ex-vivo experiment, RAW264.7 cells were cultured and treated with LPS (2 µg/ml) for 48 h while a subgroup of cells were incubated in the presence of rapamycin (50 nmol) for 2 h. Results: Continuous administration of LPS resulted in progressive macrophage infiltration, tubular injury and collagen deposition in mice kidneys. Rapamycin markedly ameliorated LPS-induced kidney pathological changes. Expression of pS6K was rarely observed in normal kidney macrophages, but significantly increased with time by LPS treatment. In ex-vivo study, LPS induced prominent production of IL-1β and MCP-1 in cultured RAW264.7 cells, which was significantly suppressed by rapamycin. Conclusion: Taken together, our findings show that endotoxemia results in activation of mTOR signaling in macrophages, leading to progressive kidney inflammatory injuries and subsequent fibrosis. Our study may reveal a mechanism involved in the development of sepsis-associated CKD and kidney fibrosis.

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Section: Discussionsupporting

confidence: 83%

Lipopolysaccharide Induces Chronic Kidney Injury and Fibrosis through Activation of mTOR Signaling in Macrophages

et al. 2015

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“…34 Our data showed that LPS induced IL1β, IL6, TNFα, and MCP1 in THP1-derived macrophages after 24 and 48 hours' stimulation, in concordance with other studies that showed a minor variation due to the activation duration and LPS concentration used. [35][36][37] As in the case of monocytes, treatment of macrophages with Lipo/GOT significantly decreased the production of cytokines IL1β, IL6, TNFα, and MCP1 induced by LPS activation compared with free GOT, which showed no effect on the secretion of cytokines in the conditioned media of macrophages.…”

Section: Discussionmentioning

confidence: 99%

Lipopolysaccharide-induced inflammation in monocytes/macrophages is blocked by liposomal delivery of G<sub>i</sub>-protein inhibitor

Pirvulescu¹,

Rebleanu²,

Constantinescu³

et al. 2017

IJN

111

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Background Lipopolysaccharide (LPS) is widely recognized as a potent activator of monocytes/macrophages, and its effects include an altered production of key mediators, such as inflammatory cytokines and chemokines. The involvement of G i protein in mediating LPS effects has been demonstrated in murine macrophages and various cell types of human origin. Purpose The aim of the present work was to evaluate the potential of a G i -protein inhibitor encapsulated in liposomes in reducing the inflammatory effects induced by LPS in monocytes/macrophages. Materials and methods Guanosine 5′- O -(2-thiodiphosphate) (GOT), a guanosine diphosphate analog that completely inhibits G-protein activation by guanosine triphosphate and its analogs, was encapsulated into liposomes and tested for anti-inflammatory effects in LPS-activated THP1 monocytes or THP1-derived macrophages. The viability of monocytes/macrophages after incubation with different concentrations of free GOT or liposome-encapsulated GOT was assessed by MTT assay. MAPK activation and production of IL1β, TNFα, IL6, and MCP1 were assessed in LPS-activated monocytes/macrophages in the presence or absence of free or encapsulated GOT. In addition, the effect of free or liposome-encapsulated GOT on LPS-stimulated monocyte adhesion to activated endothelium and on monocyte chemotaxis was evaluated. Results We report here that GOT-loaded liposomes inhibited activation of MAPK and blocked the production of the cytokines IL1β, TNFα, IL6, and MCP1 induced by LPS in monocytes and macrophages. Moreover, GOT encapsulated in liposomes reduced monocyte adhesion and chemotaxis. All demonstrated events were in contrast with free GOT, which showed reduced or no effect on monocyte/macrophage activation with LPS. Conclusion This study demonstrates the potential of liposomal GOT in blocking LPS proinflammatory effects in monocytes/macrophages.

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“…In addition to expressing CCR2 and CCR5, macrophages secret a set of chemokines which affect angiogenesis and wound healing. It was reported that Rapamycin (Rapa, an inhibitor of mTORC1) suppressed the expression of CCL2, CXCL8, CCL5, CCL8 and CCL4 in the THP-1 cells induced by LPS and human primary monocytes [14]. The stimulated production of reactive oxygen species (ROS) by phagocytic cells is necessary for the bactericidal action of phagocytes [15].…”

Section: Introductionmentioning

confidence: 99%

Tsc1 is a Critical Regulator of Macrophage Survival and Function

Fang

Luo

et al. 2015

Cell Physiol Biochem

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Background/Aims: Tuberous sclerosis complex 1 (Tsc1) has been shown to regulate M1/M2 polarization of macrophages, but the precise roles of Tsc1 in the function and stability of macrophages are not fully understood. Here we show that Tsc1 is required for regulating the survival, migration and phagocytosis of macrophages. Methods: Mice with Tsc1 homozygous deletion in myeloid cells (LysMCreTsc1^flox/flox; Tsc1 KO) were obtained by crossing Tsc1^flox/flox mice with mice expressing Cre recombinase under the control of Lysozyme promoter (LysMCre). The apoptosis and growth of macrophages were determined by flow cytometry and Real-time PCR (RT-PCR). The phagocytosis was determined using a Vybrant™ phagocytosis assay kit. The migration of macrophages was determined using transwell migration assay. Results: Peritoneal macrophages of Tsc1 KO mice exhibited increased apoptosis and enlarged cell size. Both M1 and M2 phenotypes in Tsc1-deficient macrophages were elevated in steady-state as well as in inflammatory conditions. Tsc1-deficient macrophages demonstrated impaired migration and reduced expression of chemokine receptors including CCR2 and CCR5. Phagocytosis activity and ROS production were enhanced in Tsc1-deficient macrophages. Furthermore, pharmacological inhibition of the mammalian target of rapamycin complex 1 (mTORC1) partially reversed the aberrance of Tsc1-deficient macrophages. Conclusion: Tsc1 plays a critical role in regulating macrophage survival, function and polarization via inhibition of mTORC1 activity.

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Effects of the mTOR inhibitor Rapamycin on Monocyte-Secreted Chemokines

Cited by 58 publications

References 45 publications

Lipopolysaccharide Induces Chronic Kidney Injury and Fibrosis through Activation of mTOR Signaling in Macrophages

Lipopolysaccharide Induces Chronic Kidney Injury and Fibrosis through Activation of mTOR Signaling in Macrophages

Lipopolysaccharide-induced inflammation in monocytes/macrophages is blocked by liposomal delivery of G<sub>i</sub>-protein inhibitor

Tsc1 is a Critical Regulator of Macrophage Survival and Function

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