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Immunomodulatory activity of a novel, synthetic beta-glucan (?-glu6) in murine macrophages and human peripheral blood mononuclear cells.

ABSTRACT: Natural ?-glucans extracted from plants and fungi have been used in clinical therapies since the late 20th century. However, the heterogeneity of natural ?-glucans limits their clinical applicability. We have synthesized ?-glu6, which is an analog of the lentinan basic unit, ?-(1?6)-branched ?-(1?3) glucohexaose, that contains an ?-(1?3)-linked bond. We have demonstrated the stimulatory effect of this molecule on the immune response, but the mechanisms by which ?-glu6 activates innate immunity have not been elucidated. In this study, murine macrophages and human PBMCs were used to evaluate the immunomodulatory effects of ?-glu6. We showed that ?-glu6 activated ERK and c-Raf phosphorylation but suppressed the AKT signaling pathway in murine macrophages. Additionally, ?-glu6 enhanced the secretion of large levels of cytokines and chemokines, including CD54, IL-1?, IL-1?, IL-16, IL-17, IL-23, IFN-?, CCL1, CCL3, CCL4, CCL12, CXCL10, tissue inhibitor of metalloproteinase-1 (TIMP-1) and G-CSF in murine macrophages as well as IL-6, CCL2, CCL3, CCL5, CXCL1 and macrophage migration inhibitory factor (MIF) in human PBMCs. In summary, it demonstrates the immunomodulatory activity of ?-glu6 in innate immunity.

SUBMITTER: Li X

PROVIDER: S-EPMC3819285 | biostudies-literature | 2013

REPOSITORIES: biostudies-literature

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Immunomodulatory activity of a novel, synthetic beta-glucan (β-glu6) in murine macrophages and human peripheral blood mononuclear cells.

Li Xiaofei X Wang Jing J Wang Wei W Liu Chunhong C Sun Shuhui S Gu Jianxin J Wang Xun X Boraschi Diana D Huang Yuxian Y Qu Di D

PloS one 20131106 11

Natural β-glucans extracted from plants and fungi have been used in clinical therapies since the late 20th century. However, the heterogeneity of natural β-glucans limits their clinical applicability. We have synthesized β-glu6, which is an analog of the lentinan basic unit, β-(1→6)-branched β-(1→3) glucohexaose, that contains an α-(1→3)-linked bond. We have demonstrated the stimulatory effect of this molecule on the immune response, but the mechanisms by which β-glu6 activates innate immunity h ...[more]

PMID: 24223225

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Project description:Immunomodulatory (IM) metabolic reprogramming in macrophages (Mϕs) is fundamental to immune function. However, limited information is available for human Mϕs, particularly in response plasticity, which is critical to understanding the variable efficacy of immunotherapies in cancer patients. We carried out an in-depth analysis by combining multiplex stable isotope-resolved metabolomics with reversed phase protein array to map the dynamic changes of the IM metabolic network and key protein regulators in four human donors' Mϕs in response to differential polarization and M1 repolarizer β-glucan (whole glucan particles [WGPs]). These responses were compared with those of WGP-treated ex vivo organotypic tissue cultures (OTCs) of human non-small cell lung cancer. We found consistently enhanced tryptophan catabolism with blocked NAD+ and UTP synthesis in M1-type Mϕs (M1-Mϕs), which was associated with immune activation evidenced by increased release of IL-1β/CXCL10/IFN-γ/TNF-α and reduced phagocytosis. In M2a-Mϕs, WGP treatment of M2a-Mϕs robustly increased glucose utilization via the glycolysis/oxidative branch of the pentose phosphate pathway while enhancing UDP-N-acetyl-glucosamine turnover and glutamine-fueled gluconeogenesis, which was accompanied by the release of proinflammatory IL-1β/TNF-α to above M1-Mϕ's levels, anti-inflammatory IL-10 to above M2a-Mϕ's levels, and attenuated phagocytosis. These IM metabolic responses could underlie the opposing effects of WGP, i.e., reverting M2- to M1-type immune functions but also boosting anti-inflammation. Variable reprogrammed Krebs cycle and glutamine-fueled synthesis of UTP in WGP-treated OTCs of human non-small cell lung cancer were observed, reflecting variable M1 repolarization of tumor-associated Mϕs. This was supported by correlation with IL-1β/TNF-α release and compromised tumor status, making patient-derived OTCs unique models for studying variable immunotherapeutic efficacy in cancer patients.

Dataset Information

Immunomodulatory activity of a novel, synthetic beta-glucan (?-glu6) in murine macrophages and human peripheral blood mononuclear cells.

Publications

Immunomodulatory activity of a novel, synthetic beta-glucan (β-glu6) in murine macrophages and human peripheral blood mononuclear cells.

Similar Datasets

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