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P21 mediates macrophage reprogramming through regulation of p50-p50 NF-?B and IFN-?.

ABSTRACT: M1 and M2 macrophage phenotypes, which mediate proinflammatory and antiinflammatory functions, respectively, represent the extremes of immunoregulatory plasticity in the macrophage population. This plasticity can also result in intermediate macrophage states that support a balance between these opposing functions. In sepsis, M1 macrophages can compensate for hyperinflammation by acquiring an M2-like immunosuppressed status that increases the risk of secondary infection and death. The M1 to M2 macrophage reprogramming that develops during LPS tolerance resembles the pathological antiinflammatory response to sepsis. Here, we determined that p21 regulates macrophage reprogramming by shifting the balance between active p65-p50 and inhibitory p50-p50 NF-?B pathways. p21 deficiency reduced the DNA-binding affinity of the p50-p50 homodimer in LPS-primed and -rechallenged macrophages, impairing their ability to attenuate IFN-? production and acquire an M2-like hyporesponsive status. High p21 levels in sepsis patients correlated with low IFN-? expression, and p21 knockdown in human monocytes corroborated its role in IFN-? regulation. The data demonstrate that p21 adjusts the equilibrium between p65-p50 and p50-p50 NF-?B pathways to mediate macrophage plasticity in LPS tolerance. Identifying p21-related pathways involved in monocyte reprogramming may lead to potential targets for sepsis treatment.

SUBMITTER: Rackov G

PROVIDER: S-EPMC4966310 | biostudies-literature | 2016 Aug

REPOSITORIES: biostudies-literature

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p21 mediates macrophage reprogramming through regulation of p50-p50 NF-κB and IFN-β.

Rackov Gorjana G Hernández-Jiménez Enrique E Shokri Rahman R Carmona-Rodríguez Lorena L Mañes Santos S Álvarez-Mon Melchor M López-Collazo Eduardo E Martínez-A Carlos C Balomenos Dimitrios D

The Journal of clinical investigation 20160718 8

M1 and M2 macrophage phenotypes, which mediate proinflammatory and antiinflammatory functions, respectively, represent the extremes of immunoregulatory plasticity in the macrophage population. This plasticity can also result in intermediate macrophage states that support a balance between these opposing functions. In sepsis, M1 macrophages can compensate for hyperinflammation by acquiring an M2-like immunosuppressed status that increases the risk of secondary infection and death. The M1 to M2 ma ...[more]

PMID: 27427981

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Project description:We focus on investigating the role of Parthenolide (Par), a small sesquiterpenoid molecule, in hepatocellular carcinoma (HCC) and its effective target.Highly-metastatic HCC cells, MHCC97-H, were divided into the DMSO and the Par groups, of which the Par group was intervened at 5 and 10 mg/L doses. Cell viability was assessed by CCK-8 assay. Transwell chamber assay was performed to examine the metastatic and invasive abilities, while plate clone formation assay was conducted to detect the clone formation ability. For analysis of glucose uptake, glycolytic ability and lactate level, the glycolysis assay was employed. Brdu staining was performed to evaluate the cell proliferative potential. The P50 and HIF-1α levels were measured by immunofluorescence, while the expressions of p-P50 and HIF-1α were determined by Western-Blot. Small molecule-protein docking and Pull-down experiments were conducted to validate the Par-P50 binding model. After establishing the tumor-bearing mouse model, Par was administered by gavage to measure the tissue levels of P50 and HIF-1α, followed by plotting of tumor growth curves.Par could inhibit the metastatic, invasive and clone formation abilities of MHCC97-H cells, reduce the cell proliferative potential, and suppress the glycolysis, as manifested by down-regulated level of lactate and reduced oxygen consumption. Meanwhile, Par inhibited the HIF-1α expression. We found that after silencing P50, the HIF-1α was down-regulated, the glycolytic ability decreased drastically, and the cellular metastatic and invasive abilities were suppressed. After P50 knockout, the effect of Par intervention on the MHCC97-H cells was reduced. In HCC-bearing mice, Par also exhibited an excellent anti-tumor effect, decreasing the tissue levels of P50 and HIF-1α.This study discovers that Par can inhibit the HIF-1α-mediated glycolysis of HCC cells by targeting P50, thereby exerting an anti-tumor effect. P50 is a major effective target of Par.

Dataset Information

P21 mediates macrophage reprogramming through regulation of p50-p50 NF-?B and IFN-?.

Publications

p21 mediates macrophage reprogramming through regulation of p50-p50 NF-κB and IFN-β.

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