Dataset Information

Pyruvate kinase M2 regulates Hif-1? activity and IL-1? induction and is a critical determinant of the warburg effect in LPS-activated macrophages.

ABSTRACT: Macrophages activated by the TLR4 agonist LPS undergo dramatic changes in their metabolic activity. We here show that LPS induces expression of the key metabolic regulator Pyruvate Kinase M2 (PKM2). Activation of PKM2 using two well-characterized small molecules, DASA-58 and TEPP-46, inhibited LPS-induced Hif-1? and IL-1?, as well as the expression of a range of other Hif-1?-dependent genes. Activation of PKM2 attenuated an LPS-induced proinflammatory M1 macrophage phenotype while promoting traits typical of an M2 macrophage. We show that LPS-induced PKM2 enters into a complex with Hif-1?, which can directly bind to the IL-1? promoter, an event that is inhibited by activation of PKM2. Both compounds inhibited LPS-induced glycolytic reprogramming and succinate production. Finally, activation of PKM2 by TEPP-46 in vivo inhibited LPS and Salmonella typhimurium-induced IL-1? production, while boosting production of IL-10. PKM2 is therefore a critical determinant of macrophage activation by LPS, promoting the inflammatory response.

SUBMITTER: Palsson-McDermott EM

PROVIDER: S-EPMC5198835 | biostudies-literature | 2015 Jan

REPOSITORIES: biostudies-literature

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Pyruvate kinase M2 regulates Hif-1α activity and IL-1β induction and is a critical determinant of the warburg effect in LPS-activated macrophages.

Palsson-McDermott Eva M EM Curtis Anne M AM Goel Gautam G Lauterbach Mario A R MA Sheedy Frederick J FJ Sheedy Frederick J FJ Gleeson Laura E LE van den Bosch Mirjam W M MW Quinn Susan R SR Domingo-Fernandez Raquel R Johnston Daniel G W DG Jiang Jian-Kang JK Israelsen William J WJ Keane Joseph J Thomas Craig C Clish Clary C Vander Heiden Matthew M Xavier Ramnik J RJ O'Neill Luke A J LA

Cell metabolism 20150101 1

Macrophages activated by the TLR4 agonist LPS undergo dramatic changes in their metabolic activity. We here show that LPS induces expression of the key metabolic regulator Pyruvate Kinase M2 (PKM2). Activation of PKM2 using two well-characterized small molecules, DASA-58 and TEPP-46, inhibited LPS-induced Hif-1α and IL-1β, as well as the expression of a range of other Hif-1α-dependent genes. Activation of PKM2 attenuated an LPS-induced proinflammatory M1 macrophage phenotype while promoting trai ...[more]

PMID: 25565206

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Project description:Background:Tumor-associated macrophage (TAM) is emerging as one of the important complications in cancer promotion. Interleukin-17 (IL-17), a potent pro-inflammatory cytokine, plays an active role in promoting M2 macrophage differentiation (TAMs are M2-like phenotypes). In this study, we aimed to evaluate that IL-17 stimulates key phenotypic and functional signatures of M2 macrophages associated with cancer progression in non-small-cell lung cancer (NSCLC) patients. Patients and methods:The markers and cytokines of M2 macrophages were detected in THP-1-derived macrophages and mouse peritoneal macrophages treated with IL-17. The activation of nuclear factor kappa B (NF-?B) and nuclear localization of p65 in IL-17-treated cells were investigated. The BAY11-7082 inhibitor and the siRNA of p65 were used to block the NF-?B activation. A total of 85 patients who underwent surgery for histologically verified NSCLC were enrolled in this study. The expression of IL-17 and M2 macrophage markers were assessed by immunostaining. Survivals were estimated using the Kaplan-Meier method. Results:The CD163 and CD206 cell surface markers and transforming growth factor beta (TGF-?), vascular endothelial growth factor (VEGF) and IL-10 of M2 macrophages were significantly increased in IL-17-treated THP-1-derived macrophages in a dose-dependent manner. IL-17 increased the mRNA levels of Arginase I and Fizz1, the phosphorylation of IkB? and nuclear localization of p65 (a subunit of NF-?B). The BAY11-7082 abrogated IL-17-induced CD206 and CD163 expression, TGF-?, VEGF, IL-10, Arginase I and Fizz1 expression and p65 nuclear translocation. Further experiments showed that IL-17 induced the expression of CD206, CD163, Arginase I, Fizz1 and Ym1 in mouse peritoneal macrophages that were inhibited by siRNA of p65. The immunostaining experiments on human NSCLC tissues indicated that high IL-17 expression was significantly correlated with CD163 and c-Maf. The intratumoral IL-17+ CD163+ c-Maf+ cells were associated with NSCLC progression. Conclusion:IL-17 stimulated macrophages to M2-like phenotypes via NF-?B activation. IL-17 may be a potential therapeutic target for NSCLC.

Dataset Information

Pyruvate kinase M2 regulates Hif-1? activity and IL-1? induction and is a critical determinant of the warburg effect in LPS-activated macrophages.

Publications

Pyruvate kinase M2 regulates Hif-1α activity and IL-1β induction and is a critical determinant of the warburg effect in LPS-activated macrophages.

Similar Datasets

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