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Itaconic acid is a mammalian metabolite induced during macrophage activation.

ABSTRACT: Itaconic acid (ITA), or methylenesuccinic acid, is not generally classified as a mammalian metabolite. Using NMR-based metabolomics and (13)C-labeling, we have detected ITA in both macrophage-like VM-M3 and RAW 264.7 tumor cell lines as well as stimulated and unstimulated primary murine macrophages. Macrophage activation by addition of lipopolysaccharide and IFN-? markedly increased ITA production and secretion. Crude cell extracts synthesize ITA via decarboxylation of cis-aconitate, indicative of a novel mammalian cis-aconitic decarboxylase activity. Our results highlight a previously unidentified biosynthetic pathway related to TCA cycle metabolism in mammalian cells and a novel metabolite that likely plays a role in macrophage-based immune response.

SUBMITTER: Strelko CL

PROVIDER: S-EPMC3216473 | biostudies-literature | 2011 Oct

REPOSITORIES: biostudies-literature

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Itaconic acid is a mammalian metabolite induced during macrophage activation.

Strelko Cheryl L CL Lu Wenyun W Dufort Fay J FJ Seyfried Thomas N TN Chiles Thomas C TC Rabinowitz Joshua D JD Roberts Mary F MF

Journal of the American Chemical Society 20110927 41

Itaconic acid (ITA), or methylenesuccinic acid, is not generally classified as a mammalian metabolite. Using NMR-based metabolomics and (13)C-labeling, we have detected ITA in both macrophage-like VM-M3 and RAW 264.7 tumor cell lines as well as stimulated and unstimulated primary murine macrophages. Macrophage activation by addition of lipopolysaccharide and IFN-γ markedly increased ITA production and secretion. Crude cell extracts synthesize ITA via decarboxylation of cis-aconitate, indicative ...[more]

PMID: 21919507

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| S-EPMC6118601 | biostudies-literature

Tumor-associated macrophage-derived itaconic acid contributes to nasopharyngeal carcinoma progression by promoting immune escape via TET2.

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Tolerance mechanisms towards high-temperature and -acid stress conditions during itaconic acid biosynthesis in Aspergillus terreus

2015-09-16 | GSE73033 | GEO

Macrophage Infiltration and Alternative Activation during Wound Healing Promote MEK1-Induced Skin Carcinogenesis.

Project description:Macrophages are essential for the progression and maintenance of many cancers, but their role during the earliest stages of tumor formation is unclear. To test this, we used a previously described transgenic mouse model of wound-induced skin tumorigenesis, in which expression of constitutively active MEK1 in differentiating epidermal cells results in chronic inflammation (InvEE mice). Upon wounding, the number of epidermal and dermal monocytes and macrophages increased in wild-type and InvEE skin, but the increase was greater, more rapid, and more sustained in InvEE skin. Macrophage ablation reduced tumor incidence. Furthermore, bioluminescent imaging in live mice to monitor macrophage flux at wound sites revealed that macrophage accumulation was predictive of tumor formation; wounds with the greatest number of macrophages at day 5 went on to develop tumors. Gene expression profiling of flow-sorted monocytes, macrophages, and T cells from InvEE and wild-type skin showed that as wound healing progressed, InvEE macrophages altered their phenotype. Throughout wound healing and after wound closure, InvEE macrophages demonstrated sustained upregulation of several markers implicated in alternative macrophage activation including arginase-1 (ARG1) and mannose receptor (CD206). Notably, inhibition of ARG1 activity significantly reduced tumor formation and epidermal proliferation in vivo, whereas addition of L-arginase to cultured keratinocytes stimulated proliferation. We conclude that macrophages play a key role in early, inflammation-mediated skin tumorigenesis, with mechanistic evidence suggesting that ARG1 secretion drives tumor development by stimulating epidermal cell proliferation. These findings highlight the importance of cancer immunotherapies aiming to polarize tumor-associated macrophages toward an antitumor phenotype.

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Tolerance mechanisms towards high-temperature and -acid stress conditions during itaconic acid biosynthesis in Aspergillus terreus

Project description:A. terreus LYT10 is an industrial strain for itaconic acid production, in which the biosynthesis of itaconic acid and glucose conversion rate were affected by temperature and initial concentration of itaconic acid in industrial production. RNA-seq was used to identify the key regulators related to tolerance mechanism toward various stress conditions. A total of 4 samples were analzyed. The mycelia cultivated in itaconic acid production medium (IPM) on a rotary shaker at 220 rpm and 37°C for 36 h was considered as a reference. IPMs with 5 g/L and 40 g/L itaconic acid (pH 3.25) were used for high-acid culture respectively. High-temperature condition was possesed at 42°C for 36 h in IPM.

2015-09-16 | E-GEOD-73033 | biostudies-arrayexpress

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