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Expression and localization of hepcidin in macrophages: a role in host defense against tuberculosis

Department of Microbiology, The Ohio State University, Columbus, OH 43210, USA.
Journal of Leukocyte Biology (Impact Factor: 4.3). 11/2007; 82(4):934-45. DOI: 10.1189/jlb.0407216
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ABSTRACT Hepcidin is an antimicrobial peptide produced by the liver in response to inflammatory stimuli and iron overload. Hepcidin regulates iron homeostasis by mediating the degradation of the iron export protein ferroportin 1, thereby inhibiting iron absorption from the small intestine and release of iron from macrophages. Here, we examined the expression of hepcidin in macrophages infected with the intracellular pathogens Mycobacterium avium and Mycobacterium tuberculosis. Stimulation of the mouse RAW264.7 macrophage cell line and mouse bone marrow-derived macrophages with mycobacteria and IFN-gamma synergistically induced high levels of hepcidin mRNA and protein. Similar results were obtained using the human THP-1 monocytic cell line. Stimulation of macrophages with the inflammatory cytokines IL-6 and IL-beta did not induce hepcidin mRNA expression. Iron loading inhibited hepcidin mRNA expression induced by IFN-gamma and M. avium, and iron chelation increased hepcidin mRNA expression. Intracellular protein levels and secretion of hepcidin were determined by a competitive chemiluminescence ELISA. Stimulation of RAW264.7 cells with IFN-gamma and M. tuberculosis induced intracellular expression and secretion of hepcidin. Furthermore, confocal microscopy analyses showed that hepcidin localized to the mycobacteria-containing phagosomes. As hepcidin has been shown to possess direct antimicrobial activity, we investigated its activity against M. tuberculosis. We found that hepcidin inhibited M. tuberculosis growth in vitro and caused structural damage to the mycobacteria. In summary, our data show for the first time that hepcidin localizes to the phagosome of infected, IFN-gamma-activated cells and has antimycobacterial activity.

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Available from: William C Florence, Apr 26, 2014
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    • "We think that in our severe COPD patient group, the decrease in serum hepcidin levels is related to hypoxemia rather than inflammation. In another study it was shown that hepcidin is also produced in mouse macrophages infected with intracellular Mycobacteria [28]. However, there are conflicting findings about the serum hepcidin level related to acute and chronic inflammation in the literature. "
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    ABSTRACT: Hepcidin has a regulatory role in inflammation, the immune system, and iron metabolism. It has been shown that proinflammatory cytokine interleukin 6 (IL-6) is an important inducer of hepcidin synthesis during infection and inflammation. Aim of the work To study the relationship between serum hepcidin level and hypoxemia in the COPD patients and its relation to COPD severity. Patients and methods A prospective case control study to compare serum hepcidin levels and other parameters in 70 COPD patients treated at the Pulmonology Department, King Fahad Hospital Dammam, with 34 age and sex matched healthy controls. All subjects participating in the study underwent a complete physical examination and detailed pulmonary function tests (PFTs). A sample from the radial artery for arterial blood gas analysis was done. As well as a panel of other tests including hemoglobin, hematocrit (hct), Iron, CRP, ferritin and total iron binding capacity. A hepcidin prohormone enzyme immunoassay kit (RE 54051, IBL) was used for serum hepcidin measurement. Results COPD patients had significantly lower serum hepcidin level compared to the control group (204.60 ± 53.12 and 280.81 ± 50.61, respectively). Furthermore there was a significantly greater reduction in serum hepcidin level in patients with severe COPD compared to patients with mild COPD. A positive correlation was found between serum hepcidin levels and arterial oxygen saturation (SaO2, %) and FEV1 level (P = 0.005). There was a negative correlation between serum hepcidin level and the ages of patients and packs of cigarettes consumed per year (P = 0.003). Conclusion Our study demonstrated a significant reduction in serum hepcidin levels in COPD patients, and the degree of reduction correlated with the severity of COPD and hypoxemia.
    10/2014; 64(1). DOI:10.1016/j.ejcdt.2014.09.008
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    • "Hepcidin partially inhibits M. tuberculosis growth and promotes structural damage to the bacillus (Sow et al. 2007). Despite its microbicidal role, the administration of exogenous hepcidin has been shown to enhance the growth of Chlamydia spp and Legionella pneumophila in macrophages; thus, it is possible that iron sequestration inside of the cells favours pathogen survival (Paradkar et al. 2008). "
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    ABSTRACT: Iron is essential for all organisms and its availability can control the growth of microorganisms; therefore, we examined the role of iron metabolism in multibacillary (MB) leprosy, focusing on the involvement of hepcidin. Erythrograms, iron metabolism parameters, pro-inflammatory cytokines and urinary hepcidin levels were evaluated in patients with MB and matched control subjects. Hepcidin expression in MB lesions was evaluated by quantitative polymerase chain reaction. The expression of ferroportin and hepcidin was evaluated by immunofluorescence in paucibacillary and MB lesions. Analysis of hepcidin protein levels in urine and of hepcidin mRNA and protein levels in leprosy lesions and skin biopsies from healthy control subjects showed elevated hepcidin levels in MB patients. Decreases in haematologic parameters and total iron binding capacity were observed in patients with MB leprosy. Moreover, interleukin-1 beta, ferritin, soluble transferrin receptor and soluble transferrin receptor/log ferritin index values were increased in leprosy patients. Hepcidin was elevated in lepromatous lesions, whereas ferroportin was more abundant in tuberculoid lesions. In addition, hepcidin and ferroportin were not colocalised in the biopsies from leprosy lesions. Anaemia was not commonly observed in patients with MB; however, the observed changes in haematologic parameters indicating altered iron metabolism appeared to result from a mixture of anaemia of inflammation and iron deficiency. Thus, iron sequestration inside host cells might play a role in leprosy by providing an optimal environment for the bacillus.
    Memórias do Instituto Oswaldo Cruz 12/2012; 107:183-189. DOI:10.1590/S0074-02762012000900026 · 1.57 Impact Factor
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    • "Inside the mature phagolysosome, Mtb experiences the permeabilizing properties of cationic antimicrobial peptides (CAMPs) (Flannagan et al., 2009b; Purdy and Russell, 2007). The positively charged CAMPs – cathelicidin, hepcidin and ubiquitin-related peptides – gain their bactericidal activity by disrupting the negatively charged bacterial cell wall (Alonso et al., 2007; Liu et al., 2007; Sow et al., 2007). Microbes lower their affinity to CAMPs by reduction of their negative surface charge (Peschel and Sahl, 2006). "
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    ABSTRACT: Tuberculosis (TB) remains a major health threat, killing nearly 2 million individuals around this globe, annually. The only vaccine, developed almost a century ago, provides limited protection only during childhood. After decades without the introduction of new antibiotics, several candidates are currently undergoing clinical investigation. Curing TB requires prolonged combination of chemotherapy with several drugs. Moreover, monitoring the success of therapy is questionable owing to the lack of reliable biomarkers. To substantially improve the situation, a detailed understanding of the cross-talk between human host and the pathogen Mycobacterium tuberculosis (Mtb) is vital. Principally, the enormous success of Mtb is based on three capacities: first, reprogramming of macrophages after primary infection/phagocytosis to prevent its own destruction; second, initiating the formation of well-organized granulomas, comprising different immune cells to create a confined environment for the host-pathogen standoff; third, the capability to shut down its own central metabolism, terminate replication, and thereby transit into a stage of dormancy rendering itself extremely resistant to host defense and drug treatment. Here, we review the molecular mechanisms underlying these processes, draw conclusions in a working model of mycobacterial dormancy, and highlight gaps in our understanding to be addressed in future research.
    FEMS microbiology reviews 02/2012; 36(3):514-32. DOI:10.1111/j.1574-6976.2012.00331.x · 13.81 Impact Factor
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