HLA-DQA1 and HLA-DQB1 genes in Tsachilas Indians from Ecuador: new insights in population analysis by Human Leukocyte Antigens.

Human Leucocyte Antigen (HLA) loci are widely known for their role in the generation of immune responses and are often considered to be effective in reconstructing human relationships. This is due to the high degree of polymorphism and the rarity of recombination observed at HLA loci. In this study, we have made an attempt to support the potential of HLA class II loci by analysing DQA1 and DQB1 in 52 Ecuadorians with ties to the Tsachilas community. Little is known about this populations either ethnologically or historically: they are considered retaining much of the ancient Chibchan culture in spite of the lack of significant genetic characterization. A total of 21 alleles were observed, with very low heterozygosity. The obtained data were then assessed for relationship reconstruction. The compiled database of 63 populations was segregated and resolved in clusters corresponding to the ethnogeographic distribution of the populations. This analysis of Central and Southern Amerindians allowed us to support a historical hypothesis related to the origin and migration of Ecuadorian people. Indeed, the relationships with neighbour human groups, especially Cayapas and Colombians, could shed light on the genetic similarity within ancient Chibchan culture that was dispersed by tribes coming up the Barbacoas. This indicates that if an appropriate analysis was to be carried out on a set of populations representative of different geographic locations, and that analysis was properly interpreted, then there would be a high possibility that HLA class II loci could infer accurate assessments, as revealed by uniparental markers.

Genetic response to an environmental pathogenic agent: HLA-DQ and onchocerciasis in northwestern Ecuador.

The aim of this study is to explore human leukocyte antigen (HLA)-DQ variability in two populations (Cayapas Amerindians and Afro-Ecuadorians) who live near one another along the Cayapa River and who are exposed to the same environmental stresses, such as infection by Onchocerca volvulus. HLA-DQA1 and HLA-DQB1 of 149 unrelated individuals (74 Cayapas and 75 Afro-Ecuadorians) have been analyzed. HLA high-resolution molecular typing was performed by sequence-based typing, sequence-specific oligonucleotides hybridization and sequence-specific primer (SSP) amplification. The comparison between affected (cases) and unaffected people (controls) in both populations shows the key role of several HLA-DQA1 alleles in susceptibility and protection against onchocerciasis. In both populations, there is strong evidence related to the protective role of DQA1*0401 against onchocerciasis. Alleles HLA-DQA1*0102 and *0103 seem to represent risk factors in Afro-Ecuadorians, while HLA-DQA1*0301 is only a suggestive susceptibility allele in Cayapas. These findings represent new positive/negative associations with onchocerciasis in South America, whereas previous findings pertained only to African populations.

Hospital-acquired infections and leading pathogens detected in a regional university adult acute-care hospital in Genoa, Liguria, Italy: results from a prevalence study.

BACKGROUND: A prevalence study aimed to update the epidemiological scenario of Hospital-Acquired Infections (HAI) was performed at the San Martino University Hospital of Genoa, the Regional Reference Adult-care Center in Liguria, Italy, with more than 1300 beds. MATERIALS AND METHODS: The investigation was performed in all the wards, except the Psychiatric Units, between 19th March and 6Ih April, 2007, using a one-day monitoring system for each ward. International standardized criteria and definitions for the surveillance of HAI were used for the collection of data, which were recorded in specific software for subsequent consolidation, analysis and quality control. RESULTS: The hospital infection control staff actively monitored 912 inpatients: a total of 84 HAI among 72 patients were diagnosed, with an overall prevalence of infections and affected cases of 9.2% (95% CI: 7.3-11.1) and 7.9% (95% CI: 6.1-9.7), respectively. Urinary Tract Infections (UTI) (30.9%), Respiratory Tract Infections (RTI) (28.6%) and Blood Stream Infections (BSI) (21.4%) were found to be the most frequent infections. As expected, both specific prevalence and localization of HAI varied considerably between wards, with the highest values recorded in Intensive Care Units (ICU) and in Functional Rehabilitation wards. RTI (26.3%) and BSI (13.2%) were found primarily represented in ICU, while the highest values of UTI (13.3%) were registered in Functional Rehabilitation Units. Enterococcus spp. (16.8%), Candida spp. (14%), Pseudomonas spp. (12.2), Staphylococcus aureus (10.7%), Escherichia coli (10.3%) and Coagulase-negative staphylococci (CNS) (9.3%) were the most frequent pathogens isolated. The overall rate of administration of antibiotics was 55.3% and penicillin (26.7%), cephalosporins (22.8%) and fluoroquinolones (17.9%) were found to be the leading antibacterial administered. CONCLUSION: Results of the present study have been, and are currently, used for orientating surveillance and control hospital policies, planning activities according to a rational and evidence-based approach.

Regional point prevalence study of healthcare-associated infections and antimicrobial use in acute care hospitals in Liguria, Italy.

BACKGROUND: Given the importance of monitoring healthcare-associated infections (HCAIs) and the consumption of antibiotics, a regional point prevalence survey was conducted in Liguria between March and April 2016. AIM: To measure the overall prevalence of HCAI and describe the use of antibiotics in all public hospitals. METHODS: Data on risk factors and use of antibiotics were collected for each hospitalized patient. To define the variables significantly associated with HCAI, univariate and multivariate analyses were conducted. Standardized infection ratio and standardized antimicrobial use ratio were measured for each participating hospital. FINDINGS: A total of 3647 patients were enrolled. In all, 429 HCAIs were diagnosed in 376 patients, giving a prevalence of HCAI of 10.3%. Respiratory tract (21.7%) and urinary tract (20%) were the most frequent sites of infection. High rates of meticillin-resistant Staphylococcus aureus (47.4%) and Enterobacteriaceae resistant to carbapenems (26.3%) were isolated. Forty-six percent of patients received at least one antibiotic. Combinations of penicillins including ß-lactamase inhibitors (24.1%) were the most widely used; the main indication (46.7%) was the treatment of a community-acquired infection. CONCLUSION: There was an increase in HCAI prevalence compared to a similar survey conducted in 2007; however, the performance of overlapping investigations will enable more reliable considerations. Nevertheless, data on antimicrobial resistance and use of antibiotics are consistent with the national trend. Despite methodological limitations, prevalence studies are useful to monitor HCAI over time and encourage greater awareness of the problem by all stakeholders.

Transcriptional regulation of the ferritin heavy-chain gene: the activity of the CCAAT binding factor NF-Y is modulated in heme-treated Friend leukemia cells and during monocyte-to-macrophage differentiation.

The ferritin H-chain gene promoter regulation was analyzed in heme-treated Friend leukemia cells (FLCs) and during monocyte-to-macrophage differentiation. In the majority of cell lines studied, the regulation of ferritin expression was exerted mostly at the translational level. However, in differentiating erythroid cells, which must incorporate high levels of iron to sustain hemoglobin synthesis, and in macrophages, which are involved in iron storage, transcriptional regulation seemed to be a relevant mechanism. We show here that the minimum region of the ferritin H-gene promoter that is able to confer transcriptional regulation by heme in FLCs to a reporter gene is 77 nucleotides upstream of the TATA box. This cis element binds a protein complex referred to as HRF (heme-responsive factor), which is greatly enhanced both in heme-treated FLCs and during monocyte-to-macrophage differentiation. The CCAAT element present in reverse orientation in this promoter region of the ferritin H-chain gene is necessary for binding and for gene activity, since a single point mutation is able to abolish the binding of HRF and the transcriptional activity in transfected cells. By competition experiments and supershift assays, we identified the induced HRF as containing at least the ubiquitous transcription factor NF-Y. NF-Y is formed by three subunits, A, B, and C, all of which are necessary for DNA binding. Cotransfection with a transdominant negative mutant of the NF-YA subunit abolishes the transcriptional activation by heme, indicating that NF-Y plays an essential role in this activation. We have also observed a differential expression of the NF-YA subunit in heme-treated and control FLCs and during monocyte-to-macrophage differentiation.

Modulation of ferritin H-chain expression in Friend erythroleukemia cells: transcriptional and translational regulation by hemin.

The mechanisms that regulate the expression of the H chain of the iron storage protein ferritin in Friend erythroleukemia cells (FLCs) after exposure to hemin (ferric protoporphyrin IX), protoporphyrin IX, and ferric ammonium citrate (FAC) have been investigated. Administration of hemin increases the steady-state level of ferritin mRNA about 10-fold and that of ferritin protein expression 20-fold. Experiments with the transcriptional inhibitor actinomycin D and transfection studies demonstrate that the increment in cytoplasmic mRNA content results from enhanced transcription of the ferritin H-chain gene and cannot be attributed to stabilization of preexisting mRNAs. In addition to transcriptional effects, translational regulation induces the recruitment of stored mRNAs into functional polyribosomes after hemin and FAC administration, resulting in a further increase in ferritin synthesis. Administration of protoporphyrin IX to FLCs produces divergent transcriptional and translational effects. It increases transcription but appears to suppress ferritin mRNA translation. FAC treatment increases the mRNA content slightly (about twofold), and the ferritin levels rise about fivefold over the control values. We conclude that in FLCs, hemin induces ferritin H-chain biosynthesis by multiple mechanisms: a transcriptional mechanism exerted also by protoporphyrin IX and a translational one, not displayed by protoporphyrin IX but shared with FAC.

IRF-1 deficiency skews the differentiation of dendritic cells toward plasmacytoid and tolerogenic features.

Members of the IFN regulatory factors (IRFs) family are transcriptional regulators that play essential roles in the homeostasis and function of the immune system. Recent studies indicate a direct involvement of some members of the family in the development of different subsets of dendritic cells (DC). Here, we report that IRF-1 is a potent modulator of the development and functional maturation of DC. IRF-1-deficient mice (IRF-1(-/-)) exhibited a predominance of plasmacytoid DC and a selective reduction of conventional DC, especially the CD8alpha(+) subset. IRF-1(-/-) splenic DC were markedly impaired in their ability to produce proinflammatory cytokines such as IL-12. By contrast, they expressed high levels of IL-10, TGF-beta, and the tolerogenic enzyme indoleamine 2,3 dioxygenase. As a consequence, IRF-1(-/-) DC were unable to undergo full maturation and retained plasmacytoid and tolerogenic characteristics following virus infection ex vivo and in vivo. Accordingly, DC from IRF-1(-/-) mice were less efficient in stimulating the proliferation of allogeneic T cells and instead, induced an IL-10-mediated, suppressive activity in allogeneic CD4(+)CD25(+) regulatory T cells. Together, these results indicate that IRF-1 is a key regulator of DC differentiation and maturation, exerting a variety of effects on the functional activation and tolerogenic potential of these cells.

Detection of gunshot residues on cadaveric skin using sodium rhodizonate and a counterstain.

We report a staining method for cadaveric tissue using sodium rhodizonate as a skin marker for gunshot residues and a counterstain for the surrounding connective tissue. We studied six well preserved subjects who had died of close range gunshot injury. Skin fragments were removed from the bullet entrance hole including both the disrupted area and adjacent macroscopically intact tissue. Because microscopic examination of postmortem material is difficult after histomorphologic alterations already have occurred as a consequence of postmortem tissue changes, it is necessary to use a staining method that, while detecting gunshot residues, can also make skin cell constituents recognizable from both qualitative and quantitative perspectives. Triphenylmethane dyes (acid fuchsin, aniline blue WS, light green SF yellowish, brilliant green and ethyl green) have proven appropriate for the purpose.

Activation and repression of the 2-5A synthetase and p21 gene promoters by IRF-1 and IRF-2.

The Interferon Regulatory Factors-1 and -2 (IRF-1 and IRF-2) were originally identified as transcriptional regulators of the interferon (IFN) and IFN-stimulated genes. These factors also modulate immune response and play a role in cell growth regulation. In this study we analysed the effect of the ectopic expression of IRF-1 and IRF-2 on the regulation of two potential IRF target genes involved in cell growth regulation, 2-5A synthetase and p21 (WAF/CP1), both of which contain consensus binding sites for IRF family members within their promoters. Following ectopic expression, IRF-1 transactivated 2-5A synthetase and p21 genes, an effect that was counterbalanced by concomitant ectopic expression of IRF-2. These effects were mediated by direct binding of IRF to the gene promoters. A construct expressing an IRF-2 antisense (FRI-2) was able to revert the inhibitory effect of IRF-2 on the IRF-1 transactivation. IRF-1 also induced expression of its homologous repressor IRF-2 as indicated by EMSA analysis using an IRF-E probe from the IRF-2 promoter; and by cotransfection of IRF-1 together with an IRF-2 promoter CAT construct. Therefore, the induction of IRF-1 by IFNs or other stimuli acts as a transactivator of genes involved in cell growth regulation, as well as of its own repressor IRF-2, thus providing autoinhibitory regulation of IRF-1 activated genes.

HHV-8 encoded vIRF-1 represses the interferon antiviral response by blocking IRF-3 recruitment of the CBP/p300 coactivators.

Human herpes virus 8 (HHV-8) has developed unique mechanisms for altering cellular proliferative and apoptotic control pathways by incorporating viral homologs to several cellular regulatory genes into its genome. One of the important pirated genes encoded by the ORF K9 reading frame is a viral homolog of the interferon regulatory factors (IRF), a family of cellular transcription proteins that regulates expression of genes involved in pathogen response, immune modulation and cell proliferation. vIRF-1 has been shown to downregulate the interferon- and IRF-mediated transcriptional activation of ISG and murine IFNA4 gene promoters. In this study we demonstrate that vIRF-1 efficiently inhibited virus-induced expression of endogenous interferon B, CC chemokine RANTES and CXC chemokine IP-10 genes. Co-expression analysis revealed that vIRF-1 selectively blocked IRF-3 but not IRF-7-mediated transactivation. vIRF-1 was able to bind to both IRF-3 and IRF-7 in vivo as detected by coimmunoprecipitation analysis, but did not affect IRF-3 dimerization, nuclear translocation and DNA binding activity. Rather, vIRF-1 interacted with the CBP/p300 coactivators and efficiently inhibited the formation of transcriptionally competent IRF-3-CBP/p300 complexes. These results illustrate that vIRF-1 is able to block the early stages of the IFN response to virus infection by interfering with the activation of IRF-3 responsive, immediate early IFN genes.

Heterogeneity of purified cholera toxin.

The heterogeneity of Vibrio cholerae toxin, obtained from culture filtrates in homogeneous form by gel filtration and preparative disc gel electrophoresis has been studied. By means of disc electrophoresis on polyacrylamide gel cholera toxin was separated into three forms designated I (5%), II (15%) and III (80%). The toxic activity, amino acid content and molecular weight of the three forms were similar. The difference so far observed between the various electrophoretic fractions is a difference in net charge. Incubation of either cholera toxin II or cholera toxin III at relatively high pH leads to the formation of the more acidic forms. These forms, generated in vitro by deamidation of asparagine and/or glutamine residues, are indistinguishable from the toxins of similar electrophoretic mobilities isolated from crude culture filtrates.

Impaired myelopoiesis in mice devoid of interferon regulatory factor 1.

Interferon regulatory factor (IRF)-1 is a transcription factor controlling the expression of several genes, which are differentially induced depending on the cell type and signal. IRF-1 modulates multiple functions, including regulation of immune responses and host defence, cell growth, cytokine signalling and hematopoietic development. Here, we investigated the role of IRF-1 in granulocytic differentiation in mice with a null mutation in the IRF-1 gene. We show that IRF-1(-/-) bone marrow cells exhibit an increased number of immature granulocytic precursors, associated with a decreased number of mature granulocytic elements as compared to normal mice, suggestive of a defective maturation process. Clonogenetic analyses revealed a reduced number of CFU-G, CFU-M and CFU-GM colonies in IRF-1(-/-) mice, while the number of BFU-E/CFU-E colonies was unchanged. At the molecular level, the expression of CAAT-enhancer-binding protein (C/EBP)-epsilon, -alpha and PU.1 was substantially lower in the CD11b(+) cells from the bone marrow of IRF-1(-/-) mice as compared to cells from wild-type mice. These results, together with the fact that IRF-1 is markedly induced early during granulo-monocytic differentiation of CD34+ cells, highlight the pivotal role of IRF-1 in the early phases of myelopoiesis.

Interferon-gamma receptor 2 expression as the deciding factor in human T, B, and myeloid cell proliferation or death.

The heterodimeric interferon (IFN)-gamma receptor (IFN-gammaR) is formed of two chains. Here we show that the binding chain (IFN-gammaR1) was highly expressed on the membranes of T, B, and myeloid cells. Conversely, the transducing chain (IFN-gammaR2) was highly expressed on the surfaces of myeloid cells, moderately expressed on B cells, and poorly expressed on the surfaces of T cells. Differential cell membrane expression of IFN-gammaR2 determined the number of receptor complexes that transduced the IFN-gamma signal and resulted in a different response to IFN-gamma. After IFN-gamma stimulation, high IFN-gammaR2 membrane expression induced rapid activation of signal transducer and activator of transcription-1 (STAT-1) and high levels of interferon regulatory factor-1 (IRF-1), which then triggered the apoptotic program. By contrast, low cell membrane expression resulted in slow activation of STAT-1, lower levels of IRF-1, and induction of proliferation. Because the forced expression of IFN-gammaR2 on T cells switched their response to IFN-gamma from proliferative to apoptotic, we concluded that the surface expression of IFN-gammaR2 determines whether a cell stimulated by IFN-gamma undergoes proliferation or apoptosis.

IRF regulation of HIV-1 long terminal repeat activity.

Interferon (IFN) regulatory factors (IRF) constitute a family of transcriptional activators and repressors implicated in multiple biologic processes, including regulation of immune responses and host defense, cytokine signalling, cell growth regulation, and hematopoietic development. All members are characterized by well-conserved DNA binding domains at the N-terminal region that recognize similar DNA sequences termed IRF-binding element/IFN-stimulated response element (IRF-E/ISRE) present on the promoter of the IFN-alpha/beta genes and of some IFN-stimulated genes (ISG). Recently, a sequence homologous to the ISRE has been identified downstream of the 5' human immunodeficiency virus type 1 (HIV-1) long terminal repeat (LTR). This sequence is a binding site for IRF-1 and IRF-2. Deletion of the LTR-ISRE results in impaired LTR promoter activity and decreased synthesis of viral RNA and proteins. Here, we briefly summarize characteristics of IRF-1 and IRF-2 binding to the HIV-1 LTR-ISRE and the data obtained to date on the functionality of this cis-element and on the role of IRF in the regulation of HIV-1 LTR transcriptional activity.

Hemin inhibits the interferon-beta-induced antiviral state in established cell lines.

Hemin and other metalloporphyrins are known as very versatile compounds in nature, because they are able to carry out numerous functions in a free state or in association with specific proteins. When Friend murine erythroleukemia cells are treated with IFN-beta plus 100 microM hemin, the antiviral state is not observed, whereas the antiviral effect of IFN-gamma is unaffected by hemin treatment. This inhibitory effect of hemin is not restricted to erythroid cells. In fact, it is also observed in murine L929 and in human cell lines treated with IFN-beta. Neither trivalent iron in other forms nor hemin analogs (such as protoporphyrin IX or Sn(2+)-protoporphyrine IX) mimic this effect. Conversely, Co(3+)-protoporphyrin IX was as effective as hemin. At the transcriptional level, results obtained by run-on assays on nuclei from IFN-treated cells indicate that hemin does not completely inhibit IFN-beta induction of 2-5A synthetase gene(s) at 6 h of treatment but abolishes it at 24 h. In addition, hemin is able to inhibit the accumulation of IFN-induced 2-5A synthetase mRNAs. Experiments carried out to investigate the hemin effect on the early steps of the IFN signaling pathway indicate that hemin interferes with the ability of type I IFN to bind to its receptor, probably by a direct action on the IFN molecule.

Expression of wild-type and V210I mutant prion protein in human neuroblastoma cells.

The conversion of the host-encoded prion protein (PrPc) into the insoluble, protease-resistant isoform (PrPsc) is the main pathogenic mechanism of transmissible spongiform encephalopathies. They are fatal neurodegenerative disorders, which in human occur as sporadic, inherited or familial forms. These last forms are linked to insert or point mutations of PrPc which may facilitate the spontaneous conversion into PrPsc. We have established stably transfected human neuroblastoma cells (SH-SY5Y) expressing mutant V210I, or wild-type PrPc. Both proteins were expressed and attached to the cell surface. The mutation in position 210 did not alter the biochemical properties of the protein in comparison with the wild-type protein nor induced any conformational changes similar to those observed in PrPsc.

Platelet markers in suicide attempters.

1. The authors measured 3H-imipramine (3H-IMI) binding and serotonin (5HT) uptake parameters as well as sulphotransferase activity in platelets of suicide attempters. 2. Platelet 3H-IMI binding sites and 5HT uptake are related to similar sites and processes present in the brain, and sulphotransferase (ST) is an enzyme involved in the catabolism of cathecholamines. 3. The results showed the presence of a decreased density of both 3H-IMI binding and of 5HT uptake sites, with no change in ST activity in suicide attempters, as compared with healthy controls. 4. The reduced 3H-IMI binding and 5HT uptake may be related to a hypofunction of presynaptic serotonergic mechanisms which might be altered in suicidal behavior.

Six-minute walking test in cystic fibrosis adults with mild to moderate lung disease: comparison to healthy subjects.

The six-minute walking test (6MWT) has been widely utilized to evaluate global exercise capacity in patients with cystic fibrosis. The aim of this study was to assess the exercise capacity by 6MWT, measuring four outcome measures: walk distance, oxygensaturation and pulse rate during the walk, and breathlessness perception after the walk, in a group of cystic fibrosis adults with mild to moderate lung disease, and in healthy volunteers, as the control group. Moreover, the study examined the relationship between 6MWT outcome measures and pulmonary function in patients. Twenty-five adults (15 females, age range 18-39 years) with cystic fibrosis and 22 healthy volunteers (14 females, age range 20-45 years) performed a 6MWT following a standard protocol. Walk distance, oxygen saturation (SpO2) and pulse rate at rest and during walk, and breathlessness perception after walk assessed by visual analogue scale (VAS) were measured. Cystic fibrosis patients did notdiffer from healthy volunteers in walk distance (626 +/- 49 m vs. 652 +/- 46 m) and pulse rate. Patients significantly differed from healthy volunteers in SPO2 during the walk (mean SpO2) (P < 0.0001) and VAS (P < 0.0001). In patients, SPO2 during the walk significantly correlated with forced expiratory volume in 1 sec (FEV1) (P < 0.0001), residual volume (RV) (P < 0.001), resting SPO2 (base SpO2) (P < 0.001), and inspiratory capacity (IC) (P < 0.01). In addition, VAS significantly correlated with resting SPO2 (P < 0.01) and IC (P < 0.01). On the basis of regression equations by stepwise multiple regression analysis, SpO2 during walk was predicted by FEV1 (r2 = 0.60) and VAS by IC (r2 = 0.31), whereas walk distance was not reliably predicted by any assessed variables. This study showed that cystic fibrosis adults with mild to moderate lung disease covered a normal walk distance with unimpaired cardiac adaptation, but experienced a significant fall in oxygen saturation and an increased breathlessness perception during exercise. Resting pulmonary function was related to oxygen saturation and breathlessness perception during walk, but contributed significantly only tothe prediction of oxygen saturation. We suggest that 6MWT could be valuable for identifying patients who might experience oxygen desaturation and dyspnoea during demanding daily activities.

Comparison of two enteric coated microsphere preparations in the treatment of pancreatic exocrine insufficiency caused by cystic fibrosis.

BACKGROUND: Pancreatic exocrine insufficiency is a common condition in patients with cystic fibrosis. Large amounts of pancreatic enzyme supplements are required to reduce malabsorption but patient compliance is not always optimal. AIMS: To compare patients' preference and the efficacy of two enteric coated microsphere preparations in patients with cystic fibrosis. PATIENTS: Patients with pancreatic exocrine insufficiency due to cystic fibrosis. METHODS: Patients were assigned to the crossover treatment with Creon or Pancrease for 1 week and then to the alternative treatment. Patients had to follow a fixed diet (at least 2 g fat/kg) and had to assume 1000 units lipase/g fat. The evaluation parameters were: patients' preference, acceptance of therapy, stool fat excretion, stool weight, gastrointestinal symptoms, and tolerance. RESULTS AND CONCLUSIONS: Of the 33/60 patients who expressed a preference for one of the two treatments, 30 preferred Creon while only 3 patients preferred Pancrease (p<0.001). No difference between the two treatments was observed regarding stool characteristics, gastrointestinal symptoms and tolerance. The mean number of capsules taken daily was reduced by 35% with Creon. The results of this study showed a preference in favour of Creon probably due to the reduction of daily capsule intake of 35%, supporting digestion as well as Pancrease.

Differential regulation of ferritin expression in Friend leukemia cells by iron compounds.

Ferritin is an ubiquitous iron storage protein that plays a key role in determining the intracellular fate of iron. Therefore, ferritin synthesis is highly regulated by the iron status of the cell through post-transcriptional mechanisms that involve a specific high-affinity interaction between an iron-responsive element (IRE) in the 5' untranslated region of ferritin mRNA and a 98 kDa cytoplasmic protein, the iron-regulatory factor (IRF). The mechanisms that regulate the expression of the iron storage protein ferritin were investigated in erythroid (Friend erythroleukemia cell, FLC) and fibroblastic (L929 and B6) cell lines after exposure to various iron compounds. Both hemin (ferric protoporphyrin IX) and iron (as ferric ammonium citrate, FAC) were used as inducers of ferritin synthesis. Administration of hemin increases ferritin synthesis 8-12 fold both in erythroid and in non-erythroid cell lines, whereas FAC is a weak inducer of ferritin in FLC (only 5-fold). These results correlate with ferritin mRNA expression in FLC observed after hemin treatment compared to the effect exerted by FAC administration. This differential effect suggests that heme is the physiological compound able to stimulate ferritin synthesis in erythroid cell lines and that it plays an important physiological role in regulating gene expression in developing erythroid cells.