Current Drug Targets - Inflammation & Allergy - Volume 3, Issue 4, 2004

The nuclear receptor superfamily comprises a large group of transcription factors that play a key regulatory role in development and homeostasis of multicellular organisms. A special feature of nuclear receptors is their ability to bind to condensed chromatin templates, which makes them important initiators of gene transcription. Moreover, the ability of nuclear receptors to sequentially recruit a variety of transcription factors and coregulators to target promoters and to orchestrate the whole process of gene transcription confirms their biological significance and stimulates intensive research and a high level of scientific interest in this field. In this review, we summarise current knowledge regarding the structure and function of nuclear receptors as principal regulators of gene expression. Emphasis is given to the molecular mechanisms of nuclear receptor-mediated transcriptional activation and repression including recent progress made in this area.

Glucocorticoids are well known for their potent anti-inflammatory and immune-suppressive actions. Their clinical usefulness remains limited due to serious side effects that have necessitated a search for ways of improving their benefit-risk ratios. Mechanistically, glucocorticoids function by interacting with an intracellular receptor, the glucocorticoid receptor, a ligand-regulated transcription factor that positively or negatively alters the expression of specific genes. While it is well accepted that distinct negative regulatory action of this receptor forms the basis of the desired anti-inflammatory effects of glucocorticoids, not much is known about the function of the receptor that contributes to its side effects. The fact that a number of cellular metabolic control genes are positively regulated by glucocorticoids makes positive regulation of gene expression an attractive mode of action for the adverse effects. Positive regulation of gene expression by glucocorticoids, however, occurs through different mechanisms and in cell-type specific manner making it difficult to predict its possible biological effects in one single assay procedure. Recent advances in the molecular action of the receptor are gradually revealing different assays and important characteristics that can be put together in determining the physiological consequences of the different transactivation functions of the glucocorticoid receptor. These will provide invaluable source of information for the search of glucocorticoid receptor agonists with potent anti-inflammatory but reduced side effects.

While retinoids are largely used for their anti-proliferative and pro-differentiative effects, a rich body of literature suggests that retinoid nuclear receptors-related pathways can have profound influence on the outcome of immune and inflammatory reactions. Retinoid receptors related pathways modulate immune responses both at the innate and the adaptive level by altering skin barrier, neutrophil function, antibodies production, Th1 to Th2 shift, as well as induction of many regulatory cytokines. Retinoid X receptors (RXR) act functionally as homodimers or heterodimers with other members of the nuclear hormones receptor family such as retinoid acid receptors (RAR), vitamin D receptor (VDR), peroxisome proliferators activated receptor (PPAR) which are all associated with the regulation of inflammation and immunity. The existence of such heterodimers can provide a mechanism for cross-talk between hormone signalling pathways with a synergistic or additive activity on the anti-inflammatory outcome. This can be utilized in a variety of inflammatory skin disorders.

The three peroxisome proliferator-activated receptors (PPARs) isotypes (PPARα, β / δ and γ) belong to the nuclear hormone receptor family. During the last decade, they have been identified as anti-inflammatory transcription factors. Part of this regulation antiinflammatory is mediated through negative interference between PPARs and other nuclear factors such as NFκB, AP-1 and C / EBP, which regulate innate as well as adaptative immunity. In addition, the PPARs control the functions of macrophages, B cells and T cells. In this review, we summarise the pathways through which the PPARs control inflammatory responses. We also discuss the potential utilisation of PPAR specific ligands in the treatment of inflammatory diseases, such as inflammatory bowel diseases, atherosclerosis, Parkinson's and Alzheimer's diseases.

Beyond its effects on bone metabolism, calcium and phosphorus homeostasis, 1,25- dihydroxyvitamin D3 (1,25(OH)2D3, calcitriol) exerts profound effects on the immune system. We here provide an overview over the metabolism, molecular and cellular action of 1,25(OH)2D3 with particular regard to its immunomodulatory function. Effects of 1,25(OH)2D3 on the immune system are manyfold and include suppression of T cell activation, shaping of cytokine secretion patterns, induction of regulatory T cells, modulation of proliferation, and interference with apoptosis. 1,25(OH)2D3 further influences maturation, differentiation, and migration of antigen presenting cells. Altogether, its immunomodulatory potency is comparable to other established immunosuppressants without sharing their typical adverse effects. This profile makes 1,25(OH)2D3 a potential drug for the treatment of immune-mediated diseases. Yet, the major obstacle for its clinical use, its potent calcemic activity, is not overcome to date. The identification or generation of novel vitamin D derivatives with dissociated calcemic and immunomodulatory properties is therefore a major task. Its success might eventually lead to promising drugs for future therapeutic exploitation of a wide array of immune diseases, such as psoriasis, multiple sclerosis, rheumatoid arthritis, systemic lupus erythematosus, and others.

Retinoid-related orphan receptors RORα, -β, and -γ are evolutionarily related transcription factors belonging to the steroid hormone receptor superfamily. Studies of ROR mutant mice revealed that these receptors are critical in the regulation of a number of physiological processes. RORα plays a key role in the development of the cerebellum particularly in the regulation of Purkinje cell differentiation and proliferation of granule cell progenitors. RORα has also been implicated in the maintenance of bone tissue and mice deficient in RORα exhibit a greater susceptibility to atherosclerosis. RORγ is essential for lymph node organogenesis and plays a key role in the generation or survival of lymphoid tissue inducer (Lti) cells. RORγ is also critical in thymopoiesis where it controls differentiation and promotes the survival of thymocytes by positively regulating Bcl-XL expression. Several studies have indicated a regulatory role for RORs in circadian behavior. In several tissues, the expression of RORs oscillates during circadian rhythm while mice deficient in RORβ exhibit an altered circadian rhythm. RORα and RORγ have been implicated in the control of various immune responses. Mice deficient in RORγ exhibit a reduced susceptibility to allergen-induced airway inflammation while RORα null mice show a prolonged inflammatory response to lipopolysaccharide. Recent analyses of the crystal structure and transcriptional activity of RORs revealed that cholesterol and specific cholesterol derivatives behave as agonists of RORα while certain retinoids function as partial antagonists of RORβ and RORγ. These studies indicate that ROR activity and, as a consequence physiological processes regulated by RORs, can be modulated by exogenous (ant)agonists. Therefore, the discovery of new (ant)agonists may lead to the development of novel therapeutic strategies for human disease in which RORs have been implicated.

Among the numerous steroidal and orphan nuclear receptors encoded within mammalian genomes, several are involved in the regulation of apoptosis. The authors review here recent studies on members of the Nur77 family of orphan receptors including Nur77, Nurr1 and Nor-1. These transcription factors were initially identified in nerve cells, but also play key roles in the development and the effector functions of T lymphocytes and other cells and tissues. Nur77 can also act as a modulator of transcription for other orphan steroid receptors. Regulation of the Nur77 orphan receptor family members are tightly associated with transcriptional co-factors including co-repressors and co-activators. Also, one interesting aspect of the Nur77 orphan receptor family members is that depending on its location in the mitochondria or nucleus, these orphan receptors exhibit differential roles in determining cell death or cell growth. Numerous studies demonstrated the importance of Nur77 subfamily members in regulations of early embryogenesis, thymocyte negative selection, gene expression in hypothalamic-pituitary adrenal axis, chronic inflammatory response, and vascular smooth muscle cell proliferation. This review intends to integrate the importance of nuclear receptors in health and disease, and as potential targets for drug discovery by comparing the difference and similarity in the biochemical mechanisms of action used by the classic steroid / endocrine receptors and the orphan receptors to lead to identification of novel targets in manipulating the transcriptional functions and physiologic pathways for the orphan nuclear receptors.

Differential sex-specific liability to inflammatory and autoimmune diseases, and changes in symptom severity in association with physiological fluctuations in gonadal secretions are indicative of significant contribution of sex hormones to the regulation of immune responsiveness. Apart from a postulated role in sex-specific organization of the immune system during ontogeny, gonadal steroids may influence the immune response in numerous ways. This review analyzes existing concepts, experimental and clinical data, aiming at the definition of cellular and molecular mechanisms which may serve as suitable targets for discovery of immunomodulatory drugs whose principal feature is specific interaction with sex hormone receptors. Separation of immunomodulatory effects of sex steroids from those which are exerted by glucocorticoids, and subsequent identification of sex-hormone-specific molecular targets appear to be crucial for the justification of drug discovery on the basis of sex steroid receptor ligands.

Inflammatory bowel disease is a systemic illness that may involve the lung. The most frequent manifestation is bronchial inflammation and suppuration with or without bronchiectasis. Bronchoalveolar lavage data show an increase percentage of neutrophils and steroids are very effective in the majority of cases. Some patients present severe tracheal inflammation and obstruction with an inflammatory mass bulging into the tracheal lumen. Others show a small airway involvement with or without bronchiolitis obliterans organizing pneumonia pattern and have an equivocal response to steroids. In recent years many investigators demonstrated latent pulmonary involvement with a reduction in lung transfer factor and a small airways disorders.

The collagen vascular diseases are a heterogeneous group of immunologically-mediated inflammatory disorders. Frequently, these diseases affect organ systems outside the thorax as their primary manifestation, but may involve the pleura as a single presenting feature, as part of multisystem involvement, or as an isolated manifestation of a disease that is otherwise quiescent. In this article, we review the manifestations of respiratory disease caused by rheumatoid arthritis, systemic lupus erythematosus, scleroderma, polymyositis / dermatomyositis, mixed connective tissue disease, Sjogren's syndrome, Wegener's granulomatosis, and sarcoidosis.

Various pleuro-pulmonary abnormalities are known to complicate vascular collagen diseases, particularly, rheumatoid arthritis. Each component of the respiratory system is affected, either separately or in combination. Although most pulmonary complications appear in an established case of collagen vascular disease, in certain conditions, the lung disease precedes the more typical manifestation. While some complications are asymptomatic and tend to be resolved spontaneously (for e.g. pleuritis and rheumatoid nodules), others may cause severe or fatal conditions (interstitial pneumonia and constrictive bronchiolitis). The incidence of interstitial lung disease is increasing in vascular collagen disease. This may be mainly attributed to the increase use of invasive techniques such as bronchoscopy and video-assisted thoracoscopic surgery and in part due to the use of high resolution computed tomography, and functional pulmonary tests.

Insulin deficiency induces an increase in blood glucose levels that, in long run, becomes toxic for many organs and systems. Microangiopathy and derangements in the immune function are known consequences of hyperglycemia, but the way in which these systemic alterations may affect pulmonary function has been scarcely investigated. Although confirmation from large clinical trials is still to come, the diabetic disease seems to hit the pulmonary microcirculation as any other organ by increasing vessel wall thickness and impairing gas exchange, which leads to a measurable loss of function and respiratory efficiency. In addition, a diabetic lung is more susceptible to low respiratory tract infections by atypical microorganisms and more likely to host severe episodes of pneumonia than a normal, non-diabetic lung. This is a review of current knowledge on the impact of diabetes mellitus in lung health. We have paid special attention to the role of metabolic control in preventing damage to the lung by sustained hyperglycemia.

Secondary pulmonary hypertension (sPH) may develop as a result of few systemic diseases as endocrine diseases, HIV infection, collagen diseases, liver and hematological disorders. In this review we discuss the role of systemic diseases in inducing PH starting from a pathological classification.

Lymphoproliferative disorders affecting the lung are infrequent. Therefore the diagnosis is often not easy, specially when the lung is primary affected. Moreover, new clinical-pathological entities are responsible of primary lung lymphoma that require specific treatment. It is important to keep in mind the chance that lung may be involved by lymphoproliferative disorders so to avoid the mistake of the misdiagnosis of this curable diseases since sometimes they have a good prognosis and a very different management from epithelial neoplasia of the lung.