Statins induce regulatory T cell recruitment via a CCL1 dependent pathway

The statins, a group of inhibitors of the 3-hydroxy-3-methylglutaryl coenzyme A reductase, are reported to influence a variety of immune system activities through 3-hydroxy-3-methylglutaryl coenzyme A reductase-dependent and -independent mechanisms. How statin treatment regulates immune system function in vivo nonetheless remains to be fully defined. We analyzed the immunomodulatory effects of lovastatin in a Candida albicans-induced delayed-type hypersensitivity reaction in mice. In this model, lovastatin administration reduced the acute inflammatory response elicited by C. albicans challenge. This anti-inflammatory activity of lovastatin was associated with a shift from a Th1 to a Th2 immune response, as well as an increase in the percentage of regulatory T cells at the inflammation site and in the regional draining lymph node. The lovastatin-induced increase in regulatory T cells in the inflamed skin was dependent on expression of CCL1, a chemokine that is locally up-regulated by statin administration. The anti-inflammatory effect of lovastatin was abrogated in CCL1-deficient mice. These results suggest that local regulation of chemokine expression may be an important process in statin-induced modulation of the immune system.

MicroRNAs: a new class of regulatory genes affecting metabolism

MicroRNAs (miRNAs) are short noncoding RNAs that regulate gene expression by binding to target mRNAs, which leads to reduced protein synthesis and sometimes decreased steady-state mRNA levels. Although hundreds of miRNAs have been identified, much less is known about their biological function. Several studies have provided evidence that miRNAs affect pathways that are fundamental for metabolic control in higher organisms such as adipocyte and skeletal muscle differentiation. Furthermore, some miRNAs have been implicated in lipid, amino acid, and glucose homeostasis. These studies open the possibility that miRNAs may contribute to common metabolic diseases and point to novel therapeutic opportunities based on targeting of miRNAs.

Prednisolone treatment induces tolerogenic dendritic cells and a regulatory milieu in myasthenia gravis patients

FOXP3-expressing naturally occurring CD4(+)CD25(high) T regulatory cells (Treg) are relevant in the control of autoimmunity, and a defect in this cell population has been observed in several human autoimmune diseases. We hypothesized that altered functions of peripheral Treg cells might play a role in the immunopathogenesis of myasthenia gravis, a T cell-dependent autoimmune disease characterized by the presence of pathogenic autoantibodies specific for the nicotinic acetylcholine receptor. We report in this study a significant decrease in the in vitro suppressive function of peripheral Treg cells isolated from myasthenia patients in comparison to those from healthy donors. Interestingly, Treg cells from prednisolone-treated myasthenia gravis patients showed an improved suppressive function compared with untreated patients, suggesting that prednisolone may play a role in the control of the peripheral regulatory network. Indeed, prednisolone treatment prevents LPS-induced maturation of monocyte-derived dendritic cells by hampering the up-regulation of costimulatory molecules and by limiting secretion of IL-12 and IL-23, and enhancing IL-10. In addition, CD4(+) T cells cultured in the presence of such tolerogenic dendritic cells are hyporesponsive and can suppress autologous CD4(+) T cell proliferation. The results shown in this study indicate that prednisolone treatment promotes an environment that favors immune regulation rather than inflammation.

Pregnancy in patients with ankylosing spondylitis: do regulatory T cells play a role?

OBJECTIVE: To investigate the numerical and functional changes of CD4+CD25(high) regulatory T (Treg) cells during pregnancy and postpartum in patients with ankylosing spondylitis (AS). METHODS: The frequency of CD4+CD25(high) T cells was determined by flow cytometry in 10 pregnant and 5 nonpregnant patients with AS as well as in 14 pregnant and 4 nonpregnant healthy controls. Pregnant individuals were investigated at the third trimester and 8 weeks postpartum. Treg cells and CD4+CD25- effector T (Teff) cells separated by fluorescence-activated cell sorting were stimulated with anti-CD3 and anti-CD28 monoclonal antibodies, alone or in coculture, to investigate proliferation and cytokine secretion. RESULTS: The frequency of CD4+CD25(high) Treg cells was significantly higher during pregnancy than postpartum in both healthy control subjects and patients with AS. In contrast to Treg cells in healthy pregnant women, Treg cells in pregnant women with AS secreted only small amounts of interleukin-10 and showed lower suppression of tumor necrosis factor alpha and interferon-gamma secretion by CD4+CD25- Teff cells. At the postpartum time point, proinflammatory cytokine levels in the Treg/Teff cell cocultures and Teff cell monocultures were significantly higher in patients with AS than in healthy controls. CONCLUSION: Pregnancy influenced the expansion and cytokine secretion of Treg cells in both patients with AS and control subjects. However, the Treg cells of pregnant patients with AS failed to support an antiinflammatory cytokine milieu, thereby possibly contributing to the persistent disease activity of AS during pregnancy.

Mechanistic insights from the crystal structures of a feast/famine regulatory protein from Mycobacterium tuberculosis H37Rv

Rv3291c gene from Mycobacterium tuberculosis codes for a transcriptional regulator belonging to the (leucine responsive regulatory protein/regulator of asparigine synthase C gene product) Lrp/AsnC-family. We have identified a novel effectorbinding site from crystal structures of the apo protein, complexes with a variety of amino acid effectors, X-ray based ligand screening and qualitative fluorescence spectroscopy experiments. The new effector site is in addition to the structural characterization of another distinct site in the protein conserved in the related AsnC-family of regulators. The structures reveal that the ligandbinding loops of two crystallographically ndependent subunits adopt different conformations to generate two distinct effector-binding sites. A change in the conformation of the binding site loop 100–106 in the B subunit is apparently necessary for octameric association and also allows the loop to interact with a bound ligand in the newly identified effector-binding site. There are four sites of each kind in the octamer and the protein preferentially binds to aromatic amino acids. While amino acids like Phe, Tyr and Trp exhibit binding to only one site, His exhibits binding to both sites. Binding of Phe is accompanied by a conformational change of 3.7A ° in the 75–83 loop, which is advantageously positioned to control formation of higher oligomers. Taken together, the present studies suggest an elegant control mechanism for global transcription regulation involving binding of ligands to the two sites, individually or collectively.

The Eyes Have It: Regulatory and Structural Changes Both Underlie Cichlid Visual Pigment Diversity

A major goal of evolutionary biology is to unravel the molecular genetic mechanisms that underlie functional diversification and adaptation. We investigated how changes in gene regulation and coding sequence contribute to sensory diversification in two replicate radiations of cichlid fishes. In the clear waters of Lake Malawi, differential opsin expression generates diverse visual systems, with sensitivities extending from the ultraviolet to the red regions of the spectrum. These sensitivities fall into three distinct clusters and are correlated with foraging habits. In the turbid waters of Lake Victoria, visual sensitivity is constrained to longer wavelengths, and opsin expression is correlated with ambient light. In addition to regulatory changes, we found that the opsins coding for the shortest-and longest-wavelength visual pigments have elevated numbers of potentially functional substitutions. Thus, we present a model of sensory evolution in which both molecular genetic mechanisms work in concert. Changes in gene expression generate large shifts in visual pigment sensitivity across the collective opsin spectral range, but changes in coding sequence appear to fine-tune visual pigment sensitivity at the short-and long-wavelength ends of this range, where differential opsin expression can no longer extend visual pigment sensitivity.

The Implementation of the Audiovisual Media Services Directive by National Regulatory Authorities National Responses to Regulatory Challenges

The Audiovisual Media Services Directive (AVMSD) which regulates broadcasting and on-demand audiovisual media services is at the nexus of current discussions about the convergence of media. The Green Paper of the Commission of April 2013 reflects the struggle of the European Union to come to terms with the phenomenon of convergence and highlights current legal uncertainties. The (theoretical) quest for an appropriate and future-oriented regulatory framework at the European level may be contrasted to the practice of national regulatory authorities. When faced with new media services and new business models, national regulators will inevitably have to make decisions and choices that take into account providers’ interests to offer their services as well as viewers’ interests to receive information. This balancing act performed by national regulators may tip towards the former or latter depending on the national legal framework; social, political and economic considerations; as well as cultural perceptions. This paper thus examines how certain rules contained in the AVMSD are applied by national regulators. It focuses first on the definition of an on-demand audiovisual media service and its scope. Second, it analyses the measures adopted with a view to protection minors in on-demand services and third discusses national approaches towards the promotion of European works in on-demand services. It aims at underlining the significance of national regulatory authorities and the guidelines these adopt to clarify the rules of a key EU Directive of the “media law acquis”.

Functional regulatory spaces

This article develops the concept of “Functional Regulatory Space” (FRS) in order to analyze the new forms of State action addressing (super) wicked problems. A FRS simultaneously spans several policy sectors, institutional territories and levels of government. It suggests integrating previous policy theories that focused on “boundary-spanning regime,” “territorial institutionalism” or multi-level governance. The FRS concept is envisaged as a Weberian “ideal-type” of State action and is applied to the empirical study of two European cases of potential FRS: the integrated management of water basins and the regulation of the European sky through functional airspace blocks. It will be concluded that the current airspace regulation does match the ideal-type of FRS any better than the water resource regulation does. The next research step consists in analyzing the genesis and institutionalization of potential FRS addressing other (super) wicked problems such as climate change and economic, security, health and immigration issues in different institutional contexts as well as at various levels of governance.

Avoidance goal pursuit depletes self-regulatory resources.

Objective Research on the strength model of self-regulation is burgeoning, but little empirical work has focused on the link between distinct types of daily goal pursuit and the depletion of self-regulatory resources. The authors conducted two studies on the link between avoidance goals and resource depletion. Method Study 1 (283 [228 female] Caucasians, ages 18–51) investigated the concurrent and longitudinal relations between avoidance goals and resource depletion over a 1-month period. Study 2 (132 [93 female] Caucasians, ages 18–49) investigated the concurrent and longitudinal relations between avoidance goals and resource depletion over a 1-month period and explored resource depletion as a mediator of the avoidance goal to subjective well-being relation. Results Studies 1 and 2 documented both a concurrent and a longitudinal negative relationship between avoidance goals and self-regulatory resources, and Study 2 additionally showed that self-regulatory resources mediate the negative link between avoidance goals and subjective well-being. Ancillary analyses demonstrated that the results observed in the two studies were independent of neuroticism. Conclusions These findings advance knowledge in both the resource depletion and avoidance goal literatures, and bolster the view that avoidance goal pursuit over time represents a self-regulatory vulnerability.