Copper chelation and interleukin-6 proinflammatory cytokine effects on expression of different proteins involved in iron metabolism in HepG2 cell line

Abstract

BackgroundIn vertebrates, there is an intimate relationship between copper and iron homeostasis. Copper deficiency, which leads to a defect in ceruloplasmin enzymatic activity, has a strong effect on iron homeostasis resulting in cellular iron retention. Much is known about the mechanisms underlying cellular iron retention under “normal” conditions, however, less is known about the effect of copper deficiency during inflammation.ResultsWe show that copper deficiency and the inflammatory cytokine interleukin-6 have different effects on the expression of proteins involved in iron and copper metabolism such as the soluble and glycosylphosphtidylinositol anchored forms of ceruloplasmin, hepcidin, ferroportin1, transferrin receptor1, divalent metal transporter1 and H-ferritin subunit. We demonstrate, using the human HepG2 cell line, that in addition to ceruloplasmin isoforms, copper deficiency affects other proteins, some posttranslationally and some at the transcriptional level. The addition of interleukin-6, moreover, has different effects on expression of ferroportin1 and ceruloplasmin, in which ferroportin1 is decreased while ceruloplasmin is increased. These effects are stronger when a copper chelating agent and IL-6 are used simultaneously.ConclusionsThese results suggest that copper chelation has effects not only on ceruloplasmin but also on other proteins involved in iron metabolism, sometimes at the mRNA level and, in inflammatory conditions, the functions of ferroportin and ceruloplasmin may be independent.

COVID-19: The Potential Role of Copper and N-acetylcysteine (NAC) in a Combination of Candidate Antiviral Treatments Against SARS-CoV-2

“…Furthermore, liver copper levels were increased in adjuvant-induced arthritis in rats during the inflammatory process (68). Another study demonstrated that elevated IL-6 levels resulted in increased levels of ceruloplasmin, the major copper-carrying protein in the blood (69).Therefore, the increase in copper levels could be related to the body's physiological reaction to fight inflammation (68). In addition, the inflammatory disease may be the result of insufficient hepatic copper repositories that cannot support an anti-inflammatory response (70).…”

“…Copper may also have a role in the immune system response to inflammation (67)(68)(69)(70)(71)(72)(73)(74). In inflammatory conditions, subjects exhibited higher mean serum copper concentrations related to disease activity (67,68).…”

Potential of Icariin Metabolites from Epimedium koreanum Nakai as Antidiabetic Therapeutic Agents

“…PTP1B is a negative regulator of the insulin metabolic pathway, and α-glucosidase promotes the absorption of carbohydrates into blood vessels by hydrolyzing oligosaccharides to glucose. Despite the identification of many potent compounds [ 38 , 39 , 40 , 41 ], it is still essential to search for new inhibitors with better safety and high efficacy. E. koreanum is used in TCM to treat impotence, female infertility, dysuria, rheumatic arthritis, geriatric depression, and angina pectoris [ 11 , 12 ].…”

Copper Homeostasis in Mammals, with Emphasis on Secretion and Excretion. A Review

“…In line with this, it has been known for some time that saliva contains a group of basic, histidine-rich peptides, histatins, that can bind with copper and are 3–4 kDa in mass [ 74 , 75 , 76 ]. They contain N-terminal amino acid residues that form the “amino terminal Cu(II), Ni(II)” (ATCUN) binding motif, first found in albumin, but bind Cu(II) with lower affinity (Kd in the range of 10 −7 –10 −8 , vs. 10 −11 or lower) [ 74 ].…”