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Ethanol exposure suppresses bone marrow-derived dendritic cell inflammatory responses independent of TLR4 expression.

ABSTRACT: Acute alcohol (ethanol) exposure is linked with increased susceptibility to infection and increased mortality in trauma and burn patients. Dendritic cells (DCs) are central mediators in innate and adaptive immune responses, and they play a role in the presentation of pathogens to adaptive immune cells. We investigated the effects of acute ethanol exposure on bone marrow-derived DC (BM-DC) responses. Total bone marrow cells, obtained from 8 to 10 week old C57BL/6 male mice, were cultured in the presence of granulocyte/monocyte-colony stimulating factor and interleukin (IL)-4 for 7 days. BM-DCs were harvested and treated with increasing doses of ethanol (50, 100, and 250?mM) at the time of, or 3?h before, lipopolysaccharide (LPS). After LPS, supernatants were collected for cytokine measurement, and cells were harvested for flow cytometry. Concurrent acute ethanol exposure and LPS treatment resulted in a dose-dependent suppression of IL-6, IL-12p40, IL-23, and IL-10. In addition, ethanol exposure before LPS dysregulated the IL-12p40/IL-23 balance and more profoundly suppressed IL-6 and IL-10 secretion by BM-DCs, as compared with cells concurrently treated with ethanol and LPS. Ethanol treatment did not affect either toll-like receptor (TLR)4 or TLR2 expression. In summary, our study demonstrates that acute ethanol exposure suppresses BM-DC LPS-induced responses, irrespective of affecting TLR4 or TLR2 expression.

SUBMITTER: Rendon JL

PROVIDER: S-EPMC3438840 | biostudies-other | 2012 Sep

REPOSITORIES: biostudies-other

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Ethanol exposure suppresses bone marrow-derived dendritic cell inflammatory responses independent of TLR4 expression.

Rendon Juan L JL Janda Brian A BA Bianco Monica E ME Choudhry Mashkoor A MA

Journal of interferon & cytokine research : the official journal of the International Society for Interferon and Cytokine Research 20120719 9

Acute alcohol (ethanol) exposure is linked with increased susceptibility to infection and increased mortality in trauma and burn patients. Dendritic cells (DCs) are central mediators in innate and adaptive immune responses, and they play a role in the presentation of pathogens to adaptive immune cells. We investigated the effects of acute ethanol exposure on bone marrow-derived DC (BM-DC) responses. Total bone marrow cells, obtained from 8 to 10 week old C57BL/6 male mice, were cultured in the p ...[more]

PMID: 22812678

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Project description:Alternative pathway NF-κB signalling regulates susceptibility towards developing inflammatory bowel disease (IBD), colitis-associated cancer and sepsis-associated intestinal epithelial cell apoptosis and shedding. However, the cell populations responsible for the perturbed alternative pathway NF-κB signalling in intestinal mucosal pathology remain unclear. In order to investigate the contribution of the epithelial compartment, we have tested whether NF-κB2 regulated transcription in intestinal epithelial cells controls the intestinal epithelial response to cytokines that are known to disrupt intestinal barrier permeability. Enteroids were generated from the proximal, middle and distal regions of small intestine (SI) from C57BL/6J wild-type mice and displayed region-specific morphology that was maintained during sub-culture. Enteroids treated with 100 ng/mL TNF were compared with corresponding regions of SI from C57BL/6J mice treated systemically with 0.33 mg/kg TNF for 1.5 h. TNF-induced apoptosis in all regions of the intestine in vitro and in vivo but resulted in Paneth cell degranulation only in proximal tissue-derived SI and enteroids. TNF also resulted in increased enteroid sphericity (quantified as circularity from two-dimensional bright field images). This response was dose and time-dependent and correlated with active caspase-3 immunopositivity. Proximal tissue-derived enteroids generated from Nfκb2-/- mice showed a significantly blunted circularity response following the addition of TNF, IFNγ, lipopolysaccharide (LPS) activated C57BL/6J-derived bone marrow-derived dendritic cells (BMDC) and secreted factors from LPS-activated BMDCs. However, Nfκb1-/- mouse-derived enteroids showed no significant changes in response to these stimuli. In conclusion, the selection of SI region is important when designing enteroid studies as region-specific identity and response to stimuli such as TNF are maintained in culture. Intestinal epithelial cells are at least partially responsible for regulating their own fate by modulating NF-κB2 signalling in response to stimuli known to be involved in multiple intestinal and systemic diseases. Future studies are warranted to investigate the therapeutic potential of intestinal epithelial NF-κB2 inhibition.

Dataset Information

Ethanol exposure suppresses bone marrow-derived dendritic cell inflammatory responses independent of TLR4 expression.

Publications

Ethanol exposure suppresses bone marrow-derived dendritic cell inflammatory responses independent of TLR4 expression.

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