The role of hepcidin during TLR4-and TRl5-mediated MM-6 cell activation.
Whida, Amal Masre
Cardiff Metropolitan University
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Iron has an important role in the survival of nearly all microorganisms, therefore, one of the strategies used by the immune system in the fight against infection is to reduce iron availability. Thus, iron regulation is part of the body's antimicrobial defence. Iron levels are regulated by hepcidin, a recently discovered peptide produced mainly by hepatocytes and considered the "master" regulator of iron metabolism in all vertebrates. Hepcidin acts by binding to the iron exporter ferroportin, which is found on the membrane of hepatocytes, macrophages, and the basolateral site of enterocytes. Hepcidin binding to ferroportin results in its internalization and degradation, thus preventing iron export and resulting in intracellular iron accumulation. Levels of hepcidin in the circulation are controlled by hypoxia, anaemia, and also by inflammation. Although the liver is the main source of hepcidin, this molecule can also be produced locally at sites of infection by inflammatory cells, including neutrophils, monocytes and macrophages, upon their interaction with microbial components. Therefore, hepcidin plays an important role at the crossroad between innate immunity, host defence and iron metabolism. Little is known however about the capacity of different microbial components to mediate hepcidin production. It is also not known whether hepcidin itself can modulate the interaction between innate immune cells and microbial components. In the present work, the capacity of hepcidin to modulate the release of pro-inflammatory cytokines by myeloid cells stimulated with microbial components was tested. To this aim, the monocytic cell line Mono Mac-6 (MM-6) was stimulated in the absence and presence of hepcidin with two microbial components: lipopolysaccharide (LPS), a Toll-like receptor (TLR) 4-specific ligand, and flagellin, a TLR5 ligand. The effect of hepcidin on microbialinduced cell activation was evaluated by determining the release of the chemokine CXCl8/interleukin(Il)-8 by using ELISA. The results showed that MM-6 cells were highly responsive to even minute amounts of LPS, but were unable to respond to flagellin under the stimulatory conditions used. Notably, hepcidin had an overall enhancing effect on the IX capacity of MM-6 cells to release CXCLS/IL-8 upon LPS stimulation. The enhancing effect of hepcidin was also observed even in the absence of exogenously added LPS, suggesting that hepcidin may also regulate the response to the minute amounts of LPS present in the cultures. Thus, the present work support the contention that an increase in intracellular MM-6 cells iron content - as a result of hepcidin-mediated ferroportin down regulation -, enhances TlR4-mediated cell activation and results in increased production of pro-inflammatory cytokines. In this way, hepcidin may influence the innate immune response.
MSc Biomedical Sciences (Biochemistry)
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