Dataset Information

Inflammatory macrophages induce Nrf2 transcription factor-dependent proteasome activity in colonic NCM460 cells and thereby confer anti-apoptotic protection.

ABSTRACT: Adaptation of epithelial cells to persistent oxidative stress plays an important role in inflammation-associated carcinogenesis. This adaptation process involves activation of Nrf2 (nuclear factor-E2-related factor-2), which has been recently shown to contribute to carcinogenesis through the induction of proteasomal gene expression and proteasome activity. To verify this possible link between inflammation, oxidative stress, and Nrf2-dependent proteasome activation, we explored the impact of inflammatory (M1) macrophages on the human colon epithelial cell line NCM460. Transwell cocultures with macrophages differentiated from granulocyte monocyte-colony-stimulating factor-treated monocytes led to an increased activity of Nrf2 in NCM460 cells along with an elevated proteasome activity. This higher proteasome activity resulted from Nrf2-dependent induction of proteasomal gene expression, as shown for the 19 and 20 S subunit proteins S5a and ?5, respectively. These effects of macrophage coculture were preceded by an increase of reactive oxygen species in cocultured NCM460 cells and could be blocked by catalase or by the reactive oxygen species scavenger Tiron, whereas transient treatment of NCM460 cells with H(2)O(2) similarly led to Nrf2-dependent proteasome activation. Through the Nrf2-dependent increase of proteasomal gene expression and proteasome activity, the sensitivity of NCM460 cells to tumor necrosis factor-related apoptosis-inducing ligand- or irinotecan-induced apoptosis declined. These findings indicate that inflammatory conditions such as the presence of M1 macrophages and the resulting oxidative stress are involved in the Nrf2-dependent gain of proteasome activity in epithelial cells, e.g. colonocytes, giving rise of greater resistance to apoptosis. This mechanism might contribute to inflammation-associated carcinogenesis, e.g. of the colon.

SUBMITTER: Sebens S

PROVIDER: S-EPMC3220482 | biostudies-literature | 2011 Nov

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Inflammatory macrophages induce Nrf2 transcription factor-dependent proteasome activity in colonic NCM460 cells and thereby confer anti-apoptotic protection.

Sebens Susanne S Bauer Iris I Geismann Claudia C Grage-Griebenow Evelin E Ehlers Stefan S Kruse Marie-Luise ML Arlt Alexander A Schäfer Heiner H

The Journal of biological chemistry 20111011 47

Adaptation of epithelial cells to persistent oxidative stress plays an important role in inflammation-associated carcinogenesis. This adaptation process involves activation of Nrf2 (nuclear factor-E2-related factor-2), which has been recently shown to contribute to carcinogenesis through the induction of proteasomal gene expression and proteasome activity. To verify this possible link between inflammation, oxidative stress, and Nrf2-dependent proteasome activation, we explored the impact of infl ...[more]

PMID: 21990354

Similar Datasets

Project description:The phagocytosis of apoptotic cells (efferocytosis) shifts macrophages to an anti-inflammatory state through a set of still poorly understood soluble and cell-bound signals. Apoptosis is a common feature of inflamed tissues, and efferocytosis by tissue macrophages is thought to promote the resolution of inflammation. However, it is not clear how the exposure of tissue macrophages to inflammatory cues (e.g., PAMPs, DAMPs) in the early stages of inflammation affects immune outcomes of macrophage-apoptotic cell interactions occurring at later stages of inflammation. To address this, we used low-dose endotoxin conditioning (LEC, 1 ng/ml LPS 18 h) of mouse resident peritoneal macrophages (RPMФ) to model the effects of suboptimal (i.e., non-tolerizing), antecedent TLR activation on macrophage inflammatory responses to apoptotic cells. Compared with unconditioned macrophages (MФ), LEC-MФ showed a significant enhancement of apoptotic cell-driven suppression of many inflammatory cytokines (e.g., TNF, MIP-1β, MCP-1). We then found that enzymatic depletion of adenosine or inhibition of the adenosine receptor A2a on LEC-MФ abrogated apoptotic cell suppression of TNF, and this suppression was entirely dependent on the ecto-enzyme CD73 (AMPadenosine) but not CD39 (ATPAMP), both of which are highly expressed on RPMФ. In addition to a requirement for CD73, we also show that Adora2a levels in macrophages are a critical determinant of TNF suppression by apoptotic cells. LEC treatment of RPMФ led to a ~3-fold increase in Adora2a and a ~28-fold increase in adenosine sensitivity. Moreover, in RAW264.7 cells, ectopic expression of both A2a and CD73 was required for TNF suppression by apoptotic cells. In mice, mild, TLR4-dependent inflammation in the lungs and peritoneum caused a rapid increase in macrophage Adora2a and Adora2b levels, and CD73 was required to limit neutrophil influx in this peritonitis model. Thus immune signaling via the CD73-A2a axis in macrophages links early inflammatory events to subsequent immune responses to apoptotic cells.

Dataset Information

Inflammatory macrophages induce Nrf2 transcription factor-dependent proteasome activity in colonic NCM460 cells and thereby confer anti-apoptotic protection.

Publications

Inflammatory macrophages induce Nrf2 transcription factor-dependent proteasome activity in colonic NCM460 cells and thereby confer anti-apoptotic protection.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets