Transferrin and ferritin response to bacterial infection: The role of the liver and brain in fish

IBMC - Instituto de Biologia Molecular e Celular, Universidade do Porto, Portugal.
Developmental and comparative immunology (Impact Factor: 2.82). 08/2009; 33(7):848-57. DOI: 10.1016/j.dci.2009.02.001
Source: PubMed


Iron is essential for growth and survival, but it is also toxic when in excess. Thus, there is a tight regulation of iron that is accomplished by the interaction of several genes including the iron transporter transferrin and iron storage protein ferritin. These genes are also known to be involved in response to infection. The aim of this study was to understand the role of transferrin and ferritin in infection and iron metabolism in fish. Thus, sea bass transferrin and ferritin H cDNAs were isolated from liver, cloned and characterized. Transferrin constitutive expression was found to be highest in the liver, but also with significant expression in the brain, particularly in the highly vascularized region connecting the inferior lobe of the hypothalamus and the saccus vasculosus. Ferritin, on the other hand, was expressed in all tested organs, but also significantly higher in the liver. Fish were subjected to either experimental bacterial infection or iron modulation and transferrin and ferritin mRNA expression levels were analyzed, along with several iron regulatory parameters. Transferrin expression was found to decrease in the liver and increase in the brain in response to infection and to increase in the liver in iron deficiency. Ferritin expression was found to inversely reflect transferrin in the liver, increasing in infection and iron overload and decreasing in iron deficiency, whereas in the brain, ferritin expression was also increased in infection. These findings demonstrate the evolutionary conservation of transferrin and ferritin dual functions in vertebrates, being involved in both the immune response and iron metabolism.

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    • "On the other hand, M2 showed contrasting expression in both tissues – a slight decrease in the liver but a significant increase in kidney. This observation was particularly interesting as to our knowledge; previous studies in vertebrate ferritin have consistently reported increased ferritin expression during an APR [50], [51]. The different expression patterns displayed between the ferritin chains (H- and M-chains) as well as the individual isoforms (M1 and M2) appear to suggest the possibility of more distinctive and complex roles for ferritin during an immune response than previously assumed. "
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    ABSTRACT: Ferritin is a highly-conserved iron-storage protein that has also been identified as an acute phase protein within the innate immune system. The iron-storage function is mediated through complementary roles played by heavy (H)-chain subunit as well as the light (L) in mammals or middle (M)-chain in teleosts, respectively. In this study, we report the identification of five ferritin subunits (H1, H2, M1, M2, M3) in the Atlantic salmon that were supported by the presence of iron-regulatory regions, gene structure, conserved domains and phylogenetic analysis. Tissue distribution analysis across eight different tissues showed that each of these isoforms is differentially expressed. We also examined the expression of the ferritin isoforms in the liver and kidney of juvenile Atlantic salmon that was challenged with Aeromonas salmonicida as well as in muscle cell culture stimulated with interleukin-1β. We found that each isoform displayed unique expression profiles, and in certain conditions the expressions between the isoforms were completely diametrical to each other. Our study is the first report of multiple ferritin isoforms from both the H- and M-chains in a vertebrate species, as well as ferritin isoforms that showed decreased expression in response to infection. Taken together, the results of our study suggest the possibility of functional differences between the H- and M-chain isoforms in terms of tissue localisation, transcriptional response to bacterial exposure and stimulation by specific immune factors.
    PLoS ONE 07/2014; 9(7):e103729. DOI:10.1371/journal.pone.0103729 · 3.23 Impact Factor
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    • "Recent reports on teleostan ferritin M and H subunits suggests that teleostan ferritins may involve in host immune responses besides its main role in iron homeostasis, further participating in host antioxidant defense (Elvitigala et al., 2013; Liu et al., 2010; Zhang et al., 2010; Zheng et al., 2010a,b). However, detailed characterizations and functional analyses of ferritin H orthologs have been performed in a limited number of teleost species including catfish (Ictalurus punctatus) (Liu et al., 2010), turbot (Scophthalmus maximus) (Zheng et al., 2010b), sea bass (Dicentrarchus labrax) (Neves et al., 2009), and the Atlantic salmon (S. salar) (Andersen et al., 1995). Therefore, our knowledge regarding teleost ferritin H orthologs is incomplete. "
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    ABSTRACT: Ferritins are iron binding proteins made out of 24 subunits, involved in iron homeostasis and metabolism in cellular environments. Here, we sought to identify and functionally characterize a one type of subunits of ferritin (ferritin H-like subunit) from rock bream (Oplegnathus fasciatus; RbFerH). The complete coding sequence of RbFerH was 531 bp in length, encoding a 177-amino acid protein with a predicted molecular mass of 20.8 kDa. The deduced protein structure possessed the domain architecture characteristic of known ferritin H subunits, including metal ligands for iron binding, a ferroxidase center, and two iron-binding region signatures. As expected, the 5' untranslated region of the RbFerH cDNA sequence contained a putative iron response element region, a characteristic regulatory element involved in its translation. The RbFerH gene comprised 5 exons and 4 introns spanning a 4195 bp region. Overexpressed recombinant RbFerH protein demonstrated prominent Fe(II) ion depriving activity, bacteriostatic properties, and protective effects against oxidative double-stranded DNA damage. Using quantitative polymerase chain reaction (qPCR), we found that RbFerH was expressed ubiquitously in the majority of physiologically important tissues in rock bream. A greater abundance of the mRNA transcripts were detected in blood and liver tissues. Upon administering different microbial pathogens and pathogen-derived mitogens, RbFerH transcription was markedly elevated in the blood of rock bream. Taken together, our findings suggest that RbFerH acts as a potent iron sequestrator in rock bream and may actively participate in antimicrobial as well as antioxidative defense.
    Developmental & Comparative Immunology 07/2014; 47(1). DOI:10.1016/j.dci.2014.07.004 · 2.82 Impact Factor
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    • "Aquatic animals require certain essential elements for normal life processes, e.g., Fe, Mn, Cu, Co and Zn (Santosh 2002). Among these elements, iron has essential roles in the growth and survival of most organisms (Neves et al. 2009) and also regulates acid– base balance in hemoglobin and many enzymes (Santosh 2002). Thus, maintaining a balance of iron in the body is important (Liu et al. 2010). "
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    ABSTRACT: In this study, full-length tilapia transferrin (OnTF) isolated from liver cDNA of Nile tilapia (Oreochromis niloticus) was found to have an open reading frame of 2,091-bp encoding 696 amino acid residues. Two additional amino acids: Gly(369) and Gly(370) were observed compared with the reported Nile tilapia transferrin protein sequence. Pre-mature protein has a predicted molecular weight of 78.2 kDa, while mature protein is 73.28 kDa in size. Comparative sequence analysis with transferrin from other species revealed two major putative iron-binding domains designated as the N-lobe and the C-lobe in accordance with the transferrin protein characteristics. The predicted tertiary structure of tilapia transferrin confirmed the presence of iron and anion-binding sites on both lobes that are conserved among transferrins from other species. Quantitative real-time PCR analysis showed significantly higher expression of tilapia transferrin gene in liver than in other tissues (p < 0.05). Transferrin expression in tilapia experimentally infected with 10(6) and 10(8) colony-forming units mL(-1) of Streptococcus agalactiae was significantly upregulated at 24 and 12 h post-infection (hpi), respectively, and decreased afterward. Iron-deficiency in serum of bacterially infected fish was detected at 48 and 24 hpi, respectively. The expression pattern of the transferrin gene and the iron levels of infected tilapia in this study were consistent with the function of transferrin in innate immunity.
    Fish Physiology and Biochemistry 04/2014; 40(5). DOI:10.1007/s10695-014-9941-8 · 1.62 Impact Factor
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