Ernst Schering Research Foundation workshop最新文献

The cytokines IL-1alpha and IL-1beta have long been known to play a profound role in inflammation, and in the past decade another cytokine, IL-18 (originally known as IGIF), has also been realized to be an IL-1 family member and to possess significant inflammatory activity. Half a dozen additional members of the IL-1 family have been identified in recent years, and given their relatedness to IL-I and IL-18, it is tempting to speculate that they too might possess inflammatory potential. We have demonstrated that certain of these cytokines can activate MAP kinases and the pathway leading to NFkappaB, via known IL-1R family members. Moreover, when overexpressed in skin, they are capable of causing an inflammatory skin condition resembling that seen in human disease.

Dilated cardiomyopathy (DCM) is a fatal myocardial disease with an incidence of 40:100,000. In recent years, viral infection as a causative agent for myocarditis followed by DCM has become a main topic of research. On the one hand, the virus violates the myocardial integrity itself; on the other hand, the virus induces inadequate local humoral and cellular defense reaction resulting in cardiomyocyte death, fibrosis, and overall cardiac dysfunction. Classical virological approaches are no longer sufficient to detect and identify the virus in the heart. The possibility of endomyocardial biopsies, as well as the further development of new high-specific and sensitive molecular approaches including real-time PCR or sequencing, allows us to detect and to identify the patient- specific causal virus and to predict the progression of disease and hopefully, in the future, to develop virus-specific treatment strategies.

The nuclear receptors are ideal targets to control the expression of specific genes with small molecules. Estrogen receptor can activate or repress transcription though a number of different pathways. As part of an effort to develop reagents that selectively target specific transcriptional regulatory pathways, analogs of 4-hydroxytamoxifen were synthesized with variations in the basic side chain. In vitro binding assays and cell-based luciferase reporter gene assays confirm that all the derivatives have high affinity for the receptor and high potency at repressing direct estrogen receptor-mediated transcription.

Niche has become the most important issue in stem cell biology, but it is still a hypothetical notion that cannot be defined in a better way than the microenvironment surrounding stem cells. Using a melanocyte stem cell system as a model, we have analyzed the cellular and molecular requirements for differentiation of quiescent stem cells. Our results demonstrate the multiple subsets within the stem cell compartment and thus suggests the complexity of niche.

We pioneered anticytokine therapy (ACT) for autoimmune diseases (ADs). In 1974, we proposed that hyperproduced interferon (IFN) can bring AD and anti-IFN can be therapeutic. In 1989, we proposed removing tumor necrosis factor (TNF)-alpha together with certain types of IFN to treat various ADs. We found IFN in patients with different ADs and conducted the first clinical trial of ACT in 1975. Anti-IFN-gamma and anti-TNF-alpha work in similar ways, but the latter brings serious complications in some patients. We obtained good, sometimes striking, therapeutic effects treating many different Th-1-mediated ADs with anti-IFN-gamma, including rheumatoid arthritis, multiple sclerosis (MS), corneal transplant rejection, and various autoimmune skin diseases such as psoriasis, alopecia areata, vitiligo, acne vulgaris, and others. Anti-IFN-gamma was in some ways superior to anti-TNF-alpha, which was ineffective in MS. Anti-IFN-gamma therapy holds great promise for treating many Th-1 ADs, especially skin diseases.

Psoriasis is a chronic autoimmune disease in which T lymphocytes are thought to be central in the pathogenesis. Recently, a T cell subset population was identified, whose role is to suppress inflammatory responses triggered by T effector cells. T cells in this new population are referred to as T regulatory cells. We studied their number and activity in psoriatic lesions and found that they are both numerically and functionally deficient in their ability to suppress the abnormally persistent psoriatic immune response. This deficiency may shed more light on the complex pathophysiology of psoriasis.

Several HDAC inhibitors that exhibit impressive anti-tumour activity are now in clinical trials. Proteins that function in the same pathways might also serve as valuable therapeutic targets. A subset of histone deacetylase activities are found to be physically associated with ATP-dependent remodelling enzymes and may assist their function. This raises the possibility that ATP-dependent remodelling enzymes should be considered as therapeutic targets. Here some of the links between ATP-dependent chromatin remodelling enzymes and cancer are reviewed.

Regulation of chromatin structure is important for the control of DNA-templated processes such as gene expression and silencing, and its dysregulation is implicated in diverse developmental and cell proliferative defects such as tumorigenesis. Covalent post-translational modifications of histones are one of the prominent means to regulate the chromatin structure. Here, we summarize findings from our lab and others regarding the interactions between different covalent modifications of histones in the budding yeast Saccharomyces cerevisiae. First, we describe the effect of histone H3 phosphorylation at residue serine 10 in transcriptional gene activation, and its histone H3 acetylation dependent and independent modes of action and downstream effects on TATA-binding protein (TBP) recruitment. Further, we review how ubiquitylation of histone H2B and its deubiquitylation by ubiquitin proteases Ubp8 and Ubp10 regulate histone H3 methylations, and consequently affect co-activator-dependent gene transcription and silent chromatin, respectively.

Targeting TNFalpha provided proof of concept for the role of pro-inflammatory cytokines in promoting cutaneous inflammation, particularly psoriasis. Recent studies have elucidated the presence of numerous cytokine and chemokine activities in psoriatic skin and synovium. There is considerable interest in the potential of such activities as novel therapeutic targets. IL-15 is an innate response cytokine that activates leukocyte subsets via binding to its unique IL-15Ralpha and shared beta and gamma chain receptors. IL-15 promotes T cell memory and sustains local T cell activation, in part via prevention of apoptosis and mediates activation of monocytes, neutrophils and NK cells. IL-15 is up-regulated in psoriatic skin and psoriatic arthritis synovium. IL-15 blockade in a murine model of psoriasis led to marked suppression of typical psoriatic skin features. Clinical intervention in other chronic inflammatory disease states is now ongoing with encouraging early efficacy, raising the possibility for the first time of targeting this novel inflammatory moiety in psoriasis.

Cardiac magnetic resonance imaging (CMR) permits a detailed look at the myocardium in patients with recent onset heart failure. Late-enhancement CMR provides information that is similar to that obtained by the naked eye of a pathologist. Myocardial scarring is endocardial in myocardial infarction, but it is epicardial in myocarditis and intramyocardial in hypertrophic cardiomyopathy. Thus, the distinction between these entities is possible by depicting scar via late-enhancement CMR and observing myocardial function by cine magnetic resonance imaging. Moreover, non-invasive follow-up--and hence observation of the healing or remodelling process--can be achieved using CMR. New CMR pulse sequences also permit depiction of myocardial oedema, which may occur early in patients with myocarditis and may be the only sign of the disease in the absence of necrosis. It is anticipated that cardiac MRI will become a standard diagnostic technique in patients with new onset of heart failure, left-ventricular hypertrophy or clinical symptoms suggestive of myocarditis.