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Characterization of Multiple Cytokine Combinations and TGF-? on Differentiation and Functions of Myeloid-Derived Suppressor Cells.

ABSTRACT: Myeloid-derived suppressor cells (MDSCs) regulate T cell immunity, and this population is a new therapeutic target for immune regulation. A previous study showed that transforming growth factor-? (TGF-?) is involved in controlling MDSC differentiation and immunoregulatory function in vivo. However, the direct effect of TGF-? on MDSCs with various cytokines has not previously been tested. Thus, we examined the effect of various cytokine combinations with TGF-? on MDSCs derived from bone marrow cells. The data show that different cytokine combinations affect the differentiation and immunosuppressive functions of MDSCs in different ways. In the presence of TGF-?, interleukin-6 (IL-6) was the most potent enhancer of MDSC function, whereas granulocyte colony-stimulating factors (G-CSF) was the most potent in the absence of TGF-?. In addition, IL-4 maintained MDSCs in an immature state with an increased expression of arginase 1 (Arg1). However, regardless of the cytokine combinations, TGF-? increased expansion of the monocytic MDSC (Mo-MDSC) population, expression of immunosuppressive molecules by MDSCs, and the ability of MDSCs to suppress CD4? T cell proliferation. Thus, although different cytokine combinations affected the MDSCs in different ways, TGF-? directly affects monocytic-MDSCs (Mo-MDSCs) expansion and MDSCs functions.

SUBMITTER: Lee CR

PROVIDER: S-EPMC5877730 | biostudies-literature | 2018 Mar

REPOSITORIES: biostudies-literature

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Characterization of Multiple Cytokine Combinations and TGF-β on Differentiation and Functions of Myeloid-Derived Suppressor Cells.

Lee Cho-Rong CR Lee Wongeun W Cho Steve K SK Park Sung-Gyoo SG

International journal of molecular sciences 20180315 3

Myeloid-derived suppressor cells (MDSCs) regulate T cell immunity, and this population is a new therapeutic target for immune regulation. A previous study showed that transforming growth factor-β (TGF-β) is involved in controlling MDSC differentiation and immunoregulatory function in vivo. However, the direct effect of TGF-β on MDSCs with various cytokines has not previously been tested. Thus, we examined the effect of various cytokine combinations with TGF-β on MDSCs derived from bone marrow ce ...[more]

PMID: 29543758

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Project description:BackgroundDiabetes is a proinflammatory state. Fibrosis of the renal glomerulus is the most common cause of end-stage renal disease. Glomerulosclerosis is caused by the accumulation of extracellular matrix (ECM) proteins in the mesangial interstitial space. Mesangial cells are unique stromal cells in the renal glomerulus that form the vascular pole of the renal corpuscle along with the mesangial matrix. Myeloid-derived suppressor cells (MDSCs) are heterogeneous immature myeloid cells that rapidly expand to regulate host immunity during inflammation, infection, and cancer. High concentrations of granulocyte-macrophage colony-stimulating factor (GM-CSF) alone or in combination with other molecules represent the most common ex-vivo protocol for differentiating MDSCs from bone marrow or from peripheral blood mononuclear cells. In this study, we analyzed and characterized the functions of MDSCs under the influence of mouse mesangial cells (MMCs) in a hyperglycemic environment and investigated whether cytokine-induced MDSCs ameliorated renal glomerulosclerosis in diabetic mice.MethodsCytokine-induced MDSCs were propagated from bone marrow cells cultured with mouse recombinant GM-CSF, IL-6, and IL-1β. Diabetic mice were induced with streptozotocin (STZ) and maintained at a blood glucose concentration exceeding 350 mg/dl. The ECM of the renal cortex and fibronectin expression of MMCs were analyzed through immunohistochemistry and western blotting. Arginase 1 and inducible NO synthase expressions of MDSCs were evaluated using quantitative reverse-transcriptase PCR. Cytokines released from MMCs were examined using a cytokine array assay.ResultsMDSCs in the diabetic mice were redistributed from the bone marrow into peripheral organs. An increase in fibronectin production was also observed in the renal glomerulus. MMCs in vitro produced more fibronectin and proinflammatory cytokines, such as macrophage inflammatory protein-2, RANTES, and stromal-cell-derived factor-1, under hyperglycemic conditions. The adoptive transfer of cytokine-induced MDSCs into STZ-induced mice normalized the glomerular filtration rate to reduce the kidney to body weight ratio and decrease fibronectin production in the renal glomerulus, ameliorating renal fibrosis. These results demonstrate the anti-inflammatory properties of cytokine-induced MDSCs and offer an alternative immunotherapy protocol for the management of diabetic nephropathy.ConclusionsThe application of cytokine-induced MDSCs provides a promising treatment for renal fibrosis and the prevention of diabetic nephropathy.

Dataset Information

Characterization of Multiple Cytokine Combinations and TGF-? on Differentiation and Functions of Myeloid-Derived Suppressor Cells.

Publications

Characterization of Multiple Cytokine Combinations and TGF-β on Differentiation and Functions of Myeloid-Derived Suppressor Cells.

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