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Ethanol affects fibroblast behavior differentially at low and high doses: A comprehensive, dose-response evaluation.

ABSTRACT: This study aims to develop a comprehensive understanding of effects of low and high doses of ethanol on cellular biochemistry and morphology. Here, fibroblast cells are exposed to ethanol of varied concentrations [0.005-10 % (v/v)] to investigate cellular activity, cytoskeletal organization, cellular stiffness, mitochondrial structure, and real-time behavior. Our results indicate a sharp difference in cellular behavior above and below 1 % ethanol concentration. A two-fold increase in MTT activity at low doses is observed, whereas at high doses it decreases. This increased activity at low doses does not involve cell proliferation changes or mitochondrial impairment, as seen at higher doses. Moreover, the study identifies different types of mitochondrial structure impairment at high doses. Morphologically, cells demonstrate a gradual change in cytoskeletal organization and an increase in cell stiffness with increase in doses. Cells exhibit adaptation to sub-toxic doses of ethanol, wherein recovery from ethanol-induced stress is a dose-dependent phenomenon. Cell survival at low doses and toxicity at higher doses are attributed to mild and strong oxidative stress, respectively. Overall, the study provides a comprehensive understanding of dose-dependent effects of ethanol, manifesting its biphasic or hormetic response, biochemically, at low doses and illustrating its toxicological effects at higher doses.

SUBMITTER: Kar N

PROVIDER: S-EPMC8296147 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Rheumatoid arthritis (RA) is a multifactorial autoimmune disease whose main hallmark is inflammation and destruction of the joints. Two cell types within the synovium that play an important role in RA are fibroblast-like synoviocytes (FLS) and macrophages. The latter innate immune cells show a high plasticity in their phenotype and are central in inflammatory processes. Low-dose radiotherapy (LD-RT) with particularly a single dose of 0.5 Gy has been demonstrated to have a positive impact on pain, inflammation, and bone in inflamed joints. We now examined for the first time how LD-RT influences FLS and bone marrow-derived macrophages in co-culture systems of an experimental model of RA to reveal further mechanisms of immune modulatory effects of low and intermediate dose of ionizing radiation. For this, the bone marrow of hTNF-α tg mice was differentiated either with cytokines to obtain key macrophage phenotypes (M0, M1, and M2) or with supernatants (SN) of untreated or irradiated FLS. Flow cytometry analyses were used to analyse the impact of radiation (0.1, 0.5, 1.0, and 2.0 Gy) on the phenotype of macrophages in the presence or absence of SN of FLS. LD-RT had no impact on cytokine-mediated macrophage polarization in M0, M1, or M2 macrophages. However, SN of irradiated FLS particularly reduced CD206 expression on macrophages. Macrophage phenotype was stable when being in contact with SN of nonirradiated FLS, but significantly increased surface expression of CD206 and slightly decreased CD80 and CD86 expression were observed when macrophage themselves were irradiated with 0.5 Gy under these microenvironmental conditions, again highlighting discontinuous dose dependencies in the low and intermediate dose range. One can conclude that FLS-dependent microenvironmental conditions have a slight influence on the modulation of macrophage phenotype under radiation exposure conditions. Future studies are needed to reveal the impact of radiation exposure on the functions of treated macrophages under such microenvironmental conditions.

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Ethanol affects fibroblast behavior differentially at low and high doses: A comprehensive, dose-response evaluation.

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