3,3'-Diindolylmethane Ameliorates Staphylococcal Enterotoxin B-Induced Acute Lung Injury through Alterations in the Expression of MicroRNA that Target Apoptosis and Cell-Cycle Arrest in Activated T Cells

Abstract

3,39-Diindolylmethane (DIM), a natural indole found in cruciferous vegetables, has significant anti-cancer and anti-inflammatory properties. In this current study, we investigated the effects of DIM on acute lung injury (ALI) induced by exposure to staphylococcal enterotoxin B (SEB). We found that pretreatment of mice with DIM led to attenuation of SEB-induced inflammation in the lungs, vascular leak, and IFN-g secretion. Additionally, DIM could induce cell-cycle arrest and cell death in SEB-activated T cells in a concentration-dependent manner. Interestingly, microRNA (miRNA) microarray analysis uncovered an altered miRNA profile in lung-infiltrating mononuclear cells after DIM treatment of SEB-exposed mice. Moreover, computational analysis of miRNA gene targets and regulation networks indicated that DIM alters miRNA in the cell death and cell-cycle progression pathways. Specifically, DIM treatment significantly downregulated several miRNA and a correlative increase associated gene targets. Furthermore, overexpression and inhibition studies demonstrated that DIM-induced cell death, at least in part, used miR-222. Collectively, these studies demonstrate for the first time that DIM treatment attenuates SEB-induced ALI and may do so through the induction of microRNAs that promote apoptosis and cell-cycle arrest in SEB-activated T cells.

Resveratrol protects mice against SEB‐induced acute lung injury and mortality by miR‐193a modulation that targets TGF‐β signalling

“…Exposure to SEB in humans can lead to food poisoning as well as fatal toxic shock. Inhalation of SEB can cause significant damage to the lungs resulting in respiratory failure . In the current study, performed with the 100% lethal dual‐exposure model to SEB, we demonstrate that treatment with RES can completely rescue the mice from mortality.…”

“…Samples were then filtered with 100‐μm cell strainers (Fisher Scientific, China). To isolate mononuclear cells from the lungs, we used Ficoll gradient Histopaque‐1077 (Sigma‐Aldrich, USA) as previously described . Isolated cells from the lungs and spleens were counted with trypan blue stain (Sigma‐Aldrich, USA) using a Neubauer haemato‐cytometer chamber (VWR Scientific, USA).…”

“…BALF was collected as previously described . Briefly, euthanized animals were perfused, and the trachea was tied with surgical silk (Ethicon, USA) at the upper region before removing the lungs from the body.…”

“…Then, the MHC‐II/SEB complex binds nonspecifically to T cells through the T‐cell receptor (TCR) and results in activation and proliferation of a large number of T cells . Inhalation of this virulent factor into the lungs leads to massive activation of infiltrating immune cells, the release of several cytokines (termed a “cytokine storm”), destruction of the lung‐barrier architecture allowing increased tissue permeability and ultimately leading to the failure of normal respiratory function . Current treatment options for this condition are limited, often consisting only of supportive care or the use of immunosuppressive drugs with various negative side effects .…”

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“…DIM has been shown to regulate immune responses and exhibit a broad range of biological activities in several disease models, including various cancers [29,30] and inflammatory diseases such as multiple sclerosis [26], colitis [25,31], and arthritis [32]. Moreover, DIM has shown potential effects against infections with enteric viruses [33] and Staphylococcus aureus [34,35]. The immunomodulatory properties of DIM are associated with its ability to regulate multiple receptors [36,37] and signaling pathways, such as JNK, p38, NF-B, AP-1, and FAK [28,32,38,39], suggesting that the anti-inflammatory properties of DIM are associated with the regulation of Tcell differentiation and inhibition of Th1/Th17 cells.…”