Current Pharmaceutical Design - Volume 10, Issue 23, 2004

The analysis of the molecular basis of autoimmune diseases is currently under intense investigation. The identification of novel mechanisms underlying the pathogenesis of these diseases generates the possibility for the development of new therapeutic agents. In this review we summarize the results leading to novel insights concerning the molecular processes involved in the pathogenesis of rheumatoid arthritis, systemic lupus erythematodes, multiple sclerosis and diabetes type 1. We focus on the role of transcription factors such as nuclear factor kappa B, activator protein 1, peroxisome proliferator-activated receptor, vitamin D receptor and the glucocorticoid receptor that mediate pro- and antiinflammatory effects and therefore represent direct or indirect targets for therapeutic intervention.

The glucocorticoid receptor (GR) is involved in the regulation of numerous physiological processes. In the immune system, it is thought to participate in lymphocyte apoptosis, T cell development and inflammatory responses. The extensive use of synthetic glucocorticoids as anti-inflammatory, immunosuppressive and anti-neoplastic drugs underscores the importance of the GR in immunomodulation. However, notwithstanding the long history of GR research and the clinical use of glucocorticoids, many questions regarding their mode of action remain. The following review summarizes the molecular genetic approaches that were taken during the last decade to answer some of these questions. The use of transgenic and knock-out mice has enabled gain-of-function and loss-of-function mutations in the GR to be generated even in restricted cell-types. Furthermore, these techniques possess the great advantage of allowing GR activities to be studied in the living animal. Many new and exciting findings have thereby been generated but despite the enormous efforts of several laboratories, a complete picture on the role of GR in the immune system is only just emerging.

The glucocorticoid receptor (GR) belongs to the steroid hormone receptor subclass of nuclear receptors and controls physiological processes through activation and repression of specific target genes. The ligand-activated receptor dimer activates gene expression by binding to specific DNA sequences (glucocorticoid response element, GRE) in the promoter regions of glucocorticoid-regulated genes. In contrast to the regulation of these classical GREs, the repression of negatively regulated target genes is mediated by negative GREs (nGRE), composite GREs or by transrepression. Due to their broad therapeutic spectrum and superior therapeutic effects glucocorticoids (GCs) are the most effective drugs used for the treatment of acute and chronic inflammatory diseases. Unfortunately, long term systemic therapy with GCs is restricted due to their metabolic side effects. It is assumed that transrepression of transcription factors such as AP-1 and NF-kB is the main mechanism by which glucocorticoids mediate their anti-inflammatory activity, whereas the side effects of GCs are mainly mediated by GR-DNA-interaction either by activation or by negative regulation of gene expression. While trans-repression has been characterized in detail, the molecular mechanisms of DNA-dependent cis-repression remain unclear. In this review, we focus on current knowledge about nGRE-mediated target gene repression and the relevance and function of these genes for glucocorticoid action. Negative GREs contribute to the regulation of the hypothalamic-pituitary-adrenal (HPA) axis (POMC and CRH), bone (osteocalcin) and skin (keratins) function, inflammation (IL-1β), angiogenesis (proliferin) and lactation (prolactin). The discovery of the underlying mechanisms, especially the comparison to positive GREs and trans-repression may help in the future to discover and analyze novel selective GR agonists.

Glucocorticoids are the first line medication used in the therapy of many severe inflammatory disorders. They exert their activity through binding to the glucocorticoid receptor, a ligand-dependent transcription factor, and result in either activation or repression of a large set of glucocorticoid responsive genes. The desired immunosuppressive effect is apparently due largely to the down-regulation of a variety of pro-inflammatory factors, whereas adverse reactions such as corticoid-induced diabetes and osteoporosis could be connected to the inappropriate activation of genes involved in the control of metabolic processes. The discovery of improved glucocorticoids, which maintain beneficial therapeutic activity together with a diminished risk of side effects, focuses on ligands that lead to repression rather than activation of genes targeted by the glucocorticoid receptor. Current drug-screening programs have yielded a number of molecules including steroidal as well as non-steroidal compounds, which preferentially induce receptor-mediated repression. The characterization of these novel glucocorticoids in several in vitro and in vivo models for their immune modulating activity marks an important step towards the development of a new class of safer glucocorticoid preparations.

A battery of proinflammatory agents triggers the activation of NF-κB. This inducible transcription factor participates in the expression of an exceptionally large number of target genes, many of them contributing to the regulation of innate and adaptive immunity. Since some target genes also function as NF-κB activators, activation of this transcription factor allows the establishment of a signal amplification loop. Dysregulation of the NF-κB system and hyperactivated expression of inflammatory mediators are often found in association with some autoimmune diseases, which occur upon mounting of the adaptive immune response against self-antigens. In this review we summarize the relevance of aberrant NF-κB signaling for the development and perpetuation of some autoimmune diseases such as rheumatoid arthritis, diabetes mellitus type 1 and Crohn's disease. The assets and drawbacks of systemic or cell-type specific NF-kB inhibitors and their potential use in therapy of autoimmune diseases are critically discussed.

The immune response is regulated by the concerted action of pro- and anti-inflammatory cytokines. The deregulation of this process causes immunological disorders like allergic and autoimmune diseases. The Janus Kinase (JAK) - Signal transducer and activator of transcription (STAT) pathway is one major signaling pathway converting the cytokine signal into gene expression programs regulating the proliferation and differentiation of the immune cells. Several members of the STAT protein family in particular STAT1, STAT2, STAT3, STAT4 and STAT6 act as transcription factors in modulating pro- and anti-inflammatory responses. Here we review the evidence for the involvement of the different STAT proteins in inflammation, autoimmune and allergic diseases. We discuss novel approaches to interfere with the function of these signaling transcription factors for therapeutic purpose.

The architecture of the cell nucleus has long been a matter of debate, and is still not completely understood yet. However, much progress has been made in the last few years, gradually unraveling nuclear infrastructure and its importance of the regulation of key genetic events. It is now established that the readout of genetic information and its faithful duplication are not only affected by regulatory sequences in the genome, but also by their localization in the threedimensional context and their relative position to functional subcompartments in the nucleus. Understanding how nuclear architecture and function are related and depend on each other has great potential to open up novel ways for the development of therapeutic agents. It is the purpose of this review to shed light on the role of nuclear architecture in regulating gene expression, and suggest that interfering with specific protein-protein interactions of transcription factors might provide new approaches to drug development.

Pituitary adenylate cyclase activating polypeptide (PACAP) was first isolated from hypothalamic extracts on the basis of its ability to stimulate cAMP formation in pituitary cells. PACAP is widely distributed in the central and peripheral nervous systems and exerts numerous effects. Currently available data indicate that PACAP is a promising neuroprotective peptide. PACAP plays an important role during the development of the nervous system and in regeneration following nervous injuries. It has strong anti-apoptotic effects in several neuronal cultures and in vivo. PACAP protects neurons against various toxic insults in vitro, has anti-inflammatory actions and stimulates the release of neuroprotective substances from astrocytes. In vivo, the protective effects of PACAP have been shown in various models of brain injuries, including cerebral ischemia, Parkinson's disease, trauma and nerve transections. The upregulation of PACAP following several types of nerve injuries indicates that endogenous PACAP plays a role in the post-traumatic recovery of the nervous system. The present report reviews the current knowledge on the neurotrophic and neuroprotective effects of PACAP.

Antimicrobial molecules are ancient and essential small cationic molecules of the host defence system which are found in a wide variety of species. They display antimicrobial activity against a wide range of bacteria, fungi and viruses, an activity that has been mostly attributed to the disruption of microbial membranes. In this article, we will review the “classical” functions of 3 classes of antimicrobial molecules, namely defensins, cathelicidins, and the four-disulfide core proteins secretory leukocyte proteinase inhibitor (SLPI) and elafin. In addition to the study of their expression in a variety of cell types and the regulation of their production, we will also describe novel properties of these molecules that have been highlighted by recent studies. These include their ability to chemoattract a variety of inflammatory, immune and other cell types (neutrophils, macrophages, monocytes, lymphocytes, mast cells, epithelial cells) in vitro and in vivo. In addition, we will discuss the potential use of these newly discovered properties for therapeutic or vaccination purposes, using protein- or gene-transfer based methodologies. Finally, we will examine in an extensive fashion the strategies used by microorganisms to circumvent and subvert host defence mechanisms, such as the modifications of cell membranes and walls, the secretion of inactivating proteins and proteases and the down-regulation of expression of antimicrobial molecules. Increased understanding of the mechanisms used by both the host and the microbes to ‘win the battle’ may ultimately lead to new therapeutic strategies aimed to treat infectious diseases.