β-Carotene can reverse dysregulation of iron protein in an in vitro model of inflammation

Abstract

Anemia of chronic disease is frequently seen in chronic inflammatory conditions. Its hallmark is disrupted iron homeostasis, with increased uptake and retention of iron in cells of the reticuloendothelial system. Using the Caco-2 cell line as an in vitro model for iron absorption, local intestinal iron-related protein dynamics were evaluated during interleukin (IL)1β/iron-induced inflammation, confirmed by IL8 release, and following β-carotene and vitamin A supplementation. Time- and dose-dependent iron administration to the cells was then studied. The effects on heavy and light ferritin, ferroportin, transferrin receptor and intracellular iron levels were compared in inflamed Caco-2 cells with and without application of the anti-inflammatory agents β-carotene and vitamin A. IL1β treatment led to IL8 release, a surge in both ferritins' expressions and suppression of ferroportin and transferrin receptor expression. β-Carotene significantly reduced IL8 (1,306.2-253.75 pg/ml), decreased light and heavy ferritin by 77.8 and 45.8%, respectively, and increased ferroportin by 59.9% (P < 0.05). Increasing iron concentrations and incubation periods resulted in increased IL8 release. A strong correlation was found between the levels of IL8 and the ferritins. Intracellular iron sequestration was induced by IL1β and iron and alleviated by β-carotene. β-Carotene normalized the main iron-related proteins' levels, reduced IL8 production, and released intracellular trapped iron. These results highlight local mucosal control of iron regulation and suggest that by applying anti-inflammatory compounds, less iron is locked in inflamed intestinal epithelial cells, leading to its increased bioavailability. This suggests a possible approach to combating anemia associated with chronic inflammatory conditions.

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“… 34 Initial magnesium concentration in the milk samples, and magnesium concentration after digestion, i.e., bioavailability potential, were analyzed with the ARCOS inductively coupled plasma optical emission spectrometry system (Spectro GmbH, Kleve, Germany), as described previously. 40 …”

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“…Specifically, vitamin A modulates the expression of hepatic hepcidin and ferritin in mice, and it modulates ferroportin-1 (Fpn1) expression in Caco-2 cells via a hepcidin-independent mechanism, suggesting that several mechanisms may be involved in the vitamin A‒induced regulation of iron homeostasis, including changes in hepcidin-independent iron absorption and hepcidin-dependent iron mobilization [ 79 ]. In another study, beta-carotene—the precursor of vitamin A—was found to modulate iron absorption across Caco-2 cells even in the presence of the potent pro-inflammatory ligand IL-1β [ 80 ]. Specifically, beta-carotene: (1) attenuated iron-induced IL-8 release; (2) increased intracellular ferritin levels; and (3) reduced ferroportin levels.…”

“…Specifically, beta-carotene: (1) attenuated iron-induced IL-8 release; (2) increased intracellular ferritin levels; and (3) reduced ferroportin levels. These changes resulted in normalized ferritin and ferroportin levels, reduced inflammatory signaling, and the release of intracellular trapped iron [ 80 ].…”

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“…Moreover, methanol maca leaf extract reduced lactate dehydrogenase activity and increased superoxide dismutase in PC12 cells exposed to 6-hydroxydopamine [55]. Conversely, β-carotene supplementation reduced interleukin-8 production along with normalization of light ferritin, ferroportin, and transferrin in Caco-2 cells challenged with interleukin-1β (IL-1β) to mimic the ironinduced inflammation that characterizes anemia [56]. IL-1β and tumor necrosis factor-α were conversely significantly reduced by folic acid in human promyelomonocytic cells under hypoxic conditions [57].…”