Hepcidin, a liver-derived protein that restricts enteric iron absorption, is the key regulator of body iron content. Several proteins induce expression of the hepcidin-encoding gene Hamp in response to infection or high levels of iron. However, mechanism(s) of Hamp suppression during iron depletion are poorly understood. We describe mask: a recessive, chemically induced mutant mouse phenotype, characterized by progressive loss of body (but not facial) hair and microcytic anemia. The mask phenotype results from reduced absorption of dietary iron caused by high levels of hepcidin and is due to a splicing defect in the transmembrane serine protease 6 gene Tmprss6. Overexpression of normal TMPRSS6 protein suppresses activation of the Hamp promoter, and the TMPRSS6 cytoplasmic domain mediates Hamp suppression via proximal promoter element(s). TMPRSS6 is an essential component of a pathway that detects iron deficiency and blocks Hamp transcription, permitting enhanced dietary iron absorption.

Hepcidin is a peptide that regulates iron homeostasis by inhibiting iron absorption by the small intestine and release of iron from macrophages. Its production is stimulated by iron overload and by inflammation. It has been suggested that IL-6 is the only cytokine that stimulates hepcidin transcription. However, mice with targeted disruption of the gene encoding IL-6 (IL-6 ؊/؊ ) respond to endotoxin by increasing the expression of hepcidin transcripts in the liver. We show that incubating murine hepatocytes with IL-6, IL-1␣, and IL-1␤ strongly stimulates hepcidin transcription. IL-10 has little or no stimulatory effect, and IFN-␤ inhibits transcription of hepcidin. All of the hepcidin stimulatory activity of macrophages from IL-6 ؊/؊ mice can be accounted for by IL-1 that they secrete. Hepatocytes from IL-6 ؊/؊ mice, hfe ؊/؊ mice, and mice with a hypomorphic transferrin receptor 2 mutation responded to IL-6 and IL-1 by up-regulating hepcidin transcription. Nitric oxide does not seem to be involved in the stimulation of hepcidin transcription by cytokines: aminoguanidine does not inhibit the stimulation of hepcidin transcription by cytokines. IL-1 may play a significant role in the anemia of inflammation by up-regulating hepcidin.HFE ͉ iron ͉ liver ͉ nitric oxide H epcidin has emerged as a central regulator of iron homeostasis. First described as a 25-amino acid antimicrobial peptide (1, 2), it was subsequently found to be a powerful negative regulator of iron absorption (3, 4). Befitting its role as an antimicrobial peptide, hepcidin is up-regulated in intact animals by the injection of endotoxin or turpentine.Moreover, culture media conditioned by treatment of macrophages with LPS stimulate hepcidin transcription in cultures of primary hepatocytes (5). Because this stimulation was entirely blocked by anti-IL-6 antibody, it was concluded that the stimulation was due to IL-6 and that stimulation did not occur with IL-1 and TNF-␣ (6). Our data suggested, however, that some stimulation of hepcidin production occurred in IL-6 Ϫ/Ϫ mice treated with LPS (7). These data have recently been confirmed by Rivera et al.† Accordingly, there must be substances other than IL-6 that stimulate hepcidin production. We now show that hepatocytes can be stimulated directly to produce hepcidin message by the cytokines IL-6, IL-1␣, and IL-1␤ and that the stimulation of hepcidin production by macrophage-conditioned media can be accounted for entirely by these three cytokines. Materials and MethodsAll cytokines and cytokine-specific antibodies were obtained from R & D Systems. Aminoguanidine hemisulfate was purchased from Calbiochem. IL-6 Ϫ/Ϫ mice were on a background of C57BL͞6J (002650) and were obtained from The Jackson Laboratory. hfe Ϫ/Ϫ mice and transferrin receptor 2 (tfr2) mutant mice were kind gifts from Dr. William Sly (Saint Louis University, St. Louis) and Dr. Robert Fleming (Saint Louis University), respectively. The hfe Ϫ/Ϫ mice had been backcrossed into the 129 strain for 10 generations; the tfr2 mutant mice, transgenic m...

Team leaders who facilitate knowledge sharing and engender trust contribute to team effectiveness. While the separate effects of leadership, trust and knowledge sharing on team performance are well documented, few scholars have investigated the specific links between these factors. This study examines the relationship between the leader as the knowledge builder, trust in the leader and in the team, knowledge sharing and team performance. Surveys were collected from 34 engineering project teams ( n=166 team members, 30 team leaders) and 18 managers in a large automotive organization. The results indicate that by building the team’s expertise, leaders enhance team members’ willingness to rely on and disclose information in the team, which in turn increases team knowledge sharing. Team knowledge sharing significantly predicted leaders’ and managers’ ratings of team performance. The theoretical and practical implications of the findings are discussed.

Recently, it has been suggested that hepcidin, a peptide involved in iron homeostasis, is regulated by bone morphogenetic proteins (BMPs), apparently by binding to hemojuvelin (Hjv) as a coreceptor and signaling through Smad4. We investigate the role of Hfe, Tfr2 (transferrin receptor 2), and IL-6 in BMP2-, BMP4-, and BMP9-stimulated up-regulation of murine hepcidin, because these molecules, like Hjv, are known to be involved in hepcidin signaling. We show that the BMP signaling pathway acts independently of Hfe, Tfr2, and IL-6: The response to BMP2, BMP4, and BMP9 is similar in isolated hepatocytes of wild-type, Hfe ؊/؊ , IL-6 ؊/؊ , and Tfr2 m mutant mice. The potency of different human BMPs in stimulating hepcidin transcription by murine primary hepatocytes is BMP9 > BMP4 > BMP2. However, in human HepG2 cells, BMP4 and BMP9 are equally potent, whereas BMP2 requires a higher dose to become an effective hepcidin activator. Moreover, all of the tested BMPs are more potent regulators of hepcidin than IL-6 and thus are the most potent known stimulators of hepcidin transcription.one morphogenetic proteins (BMPs) are cytokines belonging to the TGF-␤ superfamily. They play a crucial role in regulating cell proliferation, cell differentiation, and apoptosis and in the development of tissues (1, 2). There are 20 different human BMPs, with various expression profiles and tissue distribution. BMPs function by binding to specific receptors, which are divided into two separate groups: BMP receptor type I and type II. Binding to receptor homodimers is very weak, and highaffinity binding is accomplished by forming heterodimers of type I͞type II receptors (3,4).Formation of the BMP-BMP receptor I͞II type complex places these receptors in close proximity, leading to phosphorylation of the BMP type I subunit by the constitutively active serine͞threonine kinase type II receptor. Phosphorylated receptor I is an active kinase that subsequently phosphorylates intracellular messengers of BMP signaling, including the Smad proteins and mitogen-activated protein kinase (5).Smad proteins can be divided into three groups: receptormediated Smads (R-Smads) (Smad1, -2, -3, -5, and -8), the common mediator Smads (Co-Smads) (Smad4), and inhibitory Smads (Smad6 and -7). R-Smads are associated with the receptor complex and, upon ligand binding, become phosphorylated and form heterodimers with Co-Smad. The R-Smad͞Co-Smad complexes translocate to the nucleus, where they bind directly or through specific transcriptional partners to promoter sequences of the target, regulated genes that are responsible for the transcriptional response to BMPs (6).Recently, BMPs have been found to have a previously unexpected role in iron metabolism. Babitt et al. (7) demonstrated that RGMa, a homolog closely related to the protein associated with juvenile hemochromatosis (hemojuvelin, Hjv), was a coreceptor for BMP2 and BMP4. Babitt et al. (8) subsequently showed that Hjv was also a coreceptor for BMPs and suggested that the Hjv͞BMP complex regulated hepcidin expr...

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The antimicrobial peptide hepcidin appears to play a central role in the regulation of iron homeostasis. In intact animals, iron overload or the injection of lipopolysaccharide (LPS) stimulates transcription of HAMP, the gene that encodes hepcidin. In isolated hepatocytes, IL-6, an inflammatory cytokine the production of which is stimulated by LPS, up-regulates transcription of hepcidin. In contrast, iron has no stimulatory effect on hepcidin expression in isolated hepatocytes. There is apparently a signaling pathway, activated by iron, that is present in the intact animal but not in isolated hepatocytes. Studies in humans and mice have shown that this iron-dependent pathway requires the presence of Hfe, hemojuvelin, and probably transferrin receptor 2 (tfr-2). To determine whether activation of hepcidin transcription by IL-6 also requires Hfe and tfr-2, we have studied mice homozygous for targeted disruption of HFE, ␤2-microglobulin, and for a truncating mutation of TFR-2. We show that these mutant mice react normally to injection of endotoxin and that their isolated hepatocytes react normally to IL-6. This indicates that the signaling pathway activated by IL-6 does not require either Hfe or tfr-2. Mice with disruption of the gene encoding IL-6 seem to have a blunted response to LPS, but the statistical significance of the small response documented is borderline. It is therefore not clear whether LPS stimulates secretion of cytokines other than IL-6 that may stimulate hepcidin transcription.

The integrity of cerebral microvessels requires the close apposition of the endothelium to the astrocyte endfeet. Integrins alpha1beta1 and alpha6beta4 are cellular matrix receptors that may contribute to cerebral microvascular integrity. It has been hypothesized that focal ischemia alters integrin expression in a characteristic time-dependent manner consistent with neuron injury. The effects of middle cerebral artery occlusion (MCAO) and various periods of reperfusion on microvasclar integrin alpha1beta1 and alpha6beta4 expression were examined in the basal ganglia of 17 primates. Integrin subunits alpha1 and beta1 colocalized with the endothelial cell antigen CD31 in nonischemic microvessels and with glial fibrillary acidic protein on astrocyte fibers. Rapid, simultaneous, and significant disappearance of both integrin alpha1 and beta1 subunits and integrin alpha6beta4 occurred by 2 hours MCAO, which was greatest in the region of neuron injury (ischemic core, Ic), and progressively less in the peripheral (Ip) and nonischemic regions (N). Transcription of subunit beta1 mRNA on microvessels increased significantly in the Ic/Ip border and in multiple circular subregions within Ic. Microvascular integrin alpha1beta1 and integrin alpha6beta4 expression are rapidly and coordinately lost in Ic after MCAO. With loss of integrin alpha1beta1, multiple regions of microvascular beta1 mRNA up-regulation within Ic suggest that microvessel responses to focal ischemia are dynamic, and that multiple cores, not a single core, are generated. These changes imply that microvascular integrity is modified in a heterogeneous, but ordered pattern.

OBJECTIVE -To determine whether Pro-Active Call Center Treatment Support (PACCTS), using trained nonmedical telephonists supported by specially designed software and a diabetes nurse, can effectively improve glycemic control in type 2 diabetes. RESEARCH DESIGN AND METHODS -A randomized controlled implementationtrial of 1-year duration was conducted in Salford, U.K. The trial comprised 591 randomly selected individuals with type 2 diabetes. By random allocation, 197 individuals were assigned to the usual care (control) group and 394 to the PACCTS (intervention) group. Lifestyle advice and drug treatment in both groups followed local guidelines. PACCTS patients were telephoned according to a protocol with the frequency of calls proportional to the last HbA 1c level. The primary outcome was absolute reduction in HbA 1c , and the secondary outcome was the proportion of patients reducing HbA 1c by at least 1%.RESULTS -A total of 332 patients (84%) in the PACCTS group and 176 patients (89%) in the control group completed the study. Final HbA 1c values were available in 374 patients (95%) in the PACCTS group and 180 patients (92%) in the usual care group. Compared with usual care, HbA 1c improved by 0.31% (95% CI 0.11-0.52, P ϭ 0.003) overall in the PACCTS patients. For patients with baseline HbA 1c Ͼ7%, the improvement increased to 0.49% (0.21-0.77, P Ͻ 0.001), whereas in patients with baseline HbA 1c Ͻ7% there was no change. The difference in the proportions of patients achieving a Ն1% reduction in HbA 1c significantly favored the PACCTS intervention: 10% (4 -16, P Ͻ 0.001) overall and 15% (7-24, P Ͻ 0.001) for patients with baseline HbA 1c Ͼ7%.CONCLUSIONS -In an urban Caucasian trial population with blood glucose HbA 1c Ͼ7%, PACCTS facilitated significant improvement in glycemic control. Further research should extend the validity of findings to rural communities and other ethnic groups, as well as to smoking and lipid and blood pressure control. Diabetes Care 28:278 -282, 2005A worldwide epidemic of type 2 diabetes is threatening to overwhelm the capacity of health care service providers. There is good evidence that tight blood glucose, blood pressure, and lipid control can markedly reduce the adverse impact of type 2 diabetes and deliver substantial health benefits (1-4). Reviews of implementation strategies to achieve these treatment targets indicate that a multifaceted approach is most successful (5). Although a stepped-care program based on guidelines, education of primary care professionals, and support from secondary and intermediate care specialists has achieved appreciable improvements in blood pressure and lipid control in the Salford area, it has failed, thus far, to improve blood glucose control (6).Chronic disease management programs seem to be most successful when they support treatment adherence and self-efficacy (7-10). Attaining type 2 diabetes treatment targets requires appreciable pharmacologic intervention (1,3,4). However, good blood glucose control may be particularly difficult because of the s...