Neutrophil-derived cytokines: potential therapeutic targets in inflammation

Polymorphonuclear neutrophils (PMNs) are usually thought of as the leukocyte population involved in acute inflammatory responses, acting as a first line of defense against invading microorganisms. These terminally differentiated cells are generally not thought of as an important source of de novo synthesis of polypeptide mediators. Recent progress has shown, however, that PMNs are able to synthesize cytokines in response to a variety of inflammatory stimuli and during certain pathological conditions. The expression profiles of PMN-derived cytokines are similar with those of monocytes/macrophages, major professional phagocytes. Like monocytes, PMNs are able to secrete proinflammatory cytokines [e.g., tumor necrosis factor (TNF)-alpha and interleukin (IL)-1beta], both CC and CXC chemokines [e.g., IL-8, interferon-inducible protein 10 (IP-10) and macrophage inflammatory protein (MIP)-1alpha], and angiogenic factors [e.g., vascular endothelial growth factor (VEGF)]. The secretion of cytokines by activated PMNs is regulated by immunoregulatory cytokines such as interferon (IFN)-gamma, IL-4, IL-10 and IL-13. In addition to acute inflammatory responses, PMNs and PMN-derived cytokines appear to be involved in the pathogenesis of such chronic inflammatory disorders as rheumatoid arthritis, inflammatory bowel diseases and mycobacterial infections. Conceivably, these findings place PMNs at a pivotal position where they regulate and orchestrate not only acute inflammatory responses but also chronic inflammation and immune regulation. As such, inhibition of PMN-derived cytokines is viewed as a potentially useful strategy for therapeutic immunointervention.     

Potential therapeutic targets in the NF-kappaB pathway for Alzheimer's disease

One characteristic of Alzheimer's disease is a deficit in new memory formation. Numerous studies and reviews have investigated targeting the CREB pathway for enhancing memory in diseases such as Alzheimer's. In addition, the possibility of targeting the nuclear factor kappaB (NF-kappaB) pathway for inflammatory conditions, which also play a role in Alzheimer's disease, has been investigated. Interestingly, recent data concerning NF-kappaB functioning indicates that the development of drugs targeting NF-kappaB regulation may prove beneficial for memory disorders. However, given the complexity of NF-kappaB functioning, the most important challenge remaining is whether to enhance or inhibit the activation NF-kappaB. Future studies undoubtedly will focus on selected targets and "optimal activation" levels during critical stages of specific disease pathologies. This short review summarizes past studies with CREB, describes NF-kappaB functioning and highlights new data on the potential role of NF-kappaB in new memory formation and Alzheimer's disease.     

Fibroblasts as novel therapeutic targets in chronic inflammation

A characteristic feature of many chronic inflammatory diseases is their persistence and predilection for certain sites. The molecular basis for such tissue tropism and failure of the inflammatory response to resolve has until relative recently remained obscure. Recent studies have strongly implicated fibroblasts as cells which contribute to disease persistence and which help define anatomical location. Therefore fibroblasts make an attractive therapeutic target as they help orchestrate the inflammatory infiltrate. Current anti-inflammatory therapies target immune cells in an attempt to inhibit the production of pro-inflammatory mediators. However an equally important target is the active induction of pro-resolution programmes responsible for the resolution of inflammation. Fibroblasts are likely to be an important source of these anti-inflammatory mediators. Therapeutic manipulation of fibroblasts and their biologically active products is an emerging concept in treating cancer and is likely to provide a novel method to achieve improved control of chronic inflammatory disease.     

Cyclooxygenase enzymes as targets for therapeutic intervention in inflammation

The synthesis of bioactive prostanoids is controlled, in part, by the action of the cyclooxygenase (COX; prostaglandin H synthase; prostaglandin endoperoxidase) family of enzymes. Inhibition of these enzymes underlies the therapeutic action of the nonsteroidal antiinflammatory drugs (NSAIDs) and also leads to the adverse side effects, such as gastrointestinal ulceration, associated with these drugs. Interest in the therapeutic targeting of this system as a means of controlling inflammation was further expanded by the demonstration in the early 1990s of the existence of a second, inducible, isoform of COX, COX-2. Originally, it was believed that this isoform was expressed at sites of inflammation but not in noninflamed tissue, where a constitutively expressed isoform, COX-1, was thought to be responsible for the physiological production of eicosanoid mediators. This presented the opportunity to develop novel "super aspirins," which could selectively inhibit the inducible isoform, exert potently antiinflammatory effects and, importantly, be largely devoid of the deleterious side effects of conventional NSAIDs. However, it is now being increasingly accepted that COX-2 is also expressed in chronic inflammatory diseases and is seen during the resolution of inflammatory reactions and in areas undergoing wound healing. Inhibition of this isoform in these situations has revealed potential, previously hidden, pitfalls associated with COX-2 inhibition. This article examines the roles of the COX enzymes in inflammation, with emphasis on the emerging role of COX-2 during inflammatory resolution, as well as discussion of some future directions for antiinflammatory therapy that this research has suggested.     

动脉粥样硬化的分子机制及相关治疗靶点的研究进展

综合近年来有关动脉粥样硬化的认识及有治疗潜力的基因、受体、酶和活性分子的报道,从血脂异常、炎症反应、管壁细胞学、氧化应激、免疫调节、血栓形成,以及动脉粥样硬化同糖尿病和代谢综合征的关系等角度,对动脉粥样硬化发生与发展的分子机制加以综述,并且详细叙述了酰基辅酶A-胆固醇酰基转移酶、高密度脂蛋白、血凝素样氧化低密度脂蛋白受体、AMP激活的蛋白激酶、组织因子、过氧化物酶体增殖物激活受体等多个潜在的治疗靶点,为动脉粥样硬化的诊断、治疗及药物开发研究提供文献依据。     

Chemistry and biology of anti-inflammatory marine natural products: molecules interfering with cyclooxygenase, NF-kappaB and other unidentified targets

The majority of the anti-inflammatory drugs routinely used nowadays are COX (cyclo-oxygenase) inhibitors. The important role of this enzyme, once known as prostaglandin synthase, in inflammation came a consequence of the discovery by the Nobel prize winner John Vane with his path-breaking discovery that aspirin and similar drugs exert their action by blocking the biosynthesis of the prostaglandin group of lipid mediators. (John R. Vane, Nobel Lecture, December 8, 1982 and references cited therein) In the last five years it has become clear that there are two such enzymes involved. One of the "cyclo-oxygenases", called COX1 is responsible for making prostaglandins, which among other things, protect the stomach and kidney from damage. It is now clear that inhibition of COX1 accounts for the unwanted side effects of aspirin-like drugs such as gastric irritation and renal damage. The other enzyme, COX2, is induced by inflammatory stimuli and it is prostaglandins made by this enzyme that contribute to the inflammation in diseases such as rheumatoid arthritis. However, concerning inflammation-related targets, one should not limit the interest to COX and PLA2 enzymes. In recent years, it has steadily become more clear, that modulation in the expression of genes underlies most cellular responses, and inflammation is certainly not an exception in this sense. It does not come as surprise that molecules showing ability to interfere with factors involved in the modulation of genes expression, such as NF-kB, have also to be considered potential anti-inflammatory agents. Also in this respect, marine natural products (MNP) have brought a collection of novel molecular entities displaying ability to target COX1/COX2, NF-kappaB or acting through molecular mechanisms yet-to-be-discovered. Following, the marine natural products accounted for within this review will be grouped on the basis of their bio-molecular targets. Chemical synthesis of particular relevant molecules will be also discussed, especially in those cases where the natural products can be considered as lead compounds for the development of simplified derivatives or analogues of potential pharmaceutical interest.     

The potentials of selected therapeutic targets for inflammation: a snapshot

Inflammation is a complex integrated host response to infection and injury. Inflammatory cells respond to foreign substances and inflammatory stimulus by producing various chemical bioactive mediators such as prostanoids, cytokines and chemokines. These mediators have complex, pleiotropic effects and interact with many cell types and cellular pathways to amplify the inflammatory response. Dysregulation of these processes can lead to acute and chronic inflammatory diseases necessitating pharmacological intervention to attenuate cellular inflammation pathways. This review focuses on new targets and alternative approaches to the development of novel therapeutics based on the endogenous chemicals mediators and the regulation of the associated cellular pathways that modulate inflammation leading its resolution and patents relevant to these targets.     

Carbohydrate sulfotransferases: novel therapeutic targets for inflammation, viral infection and cancer

Effective direct inhibition of adhesion receptors by small molecules has been hampered by extended receptor-ligand interfaces as well as the entropic penalties often associated with inhibition of cell adhesion. Therefore, alternative strategies have targeted enzymes that are centrally involved in the biosynthesis of recognition epitopes, which are crucial for productive adhesion. Two classes of enzymes shown to play a pivotal role in cell-cell and cell-matrix adhesions are the protein-tyrosine and carbohydrate sulfotransferases, which impart crucial sulfate moieties onto glycoproteins. The carbohydrate sulfotransferases will be discussed in terms of target validation and small-molecule inhibitor discovery.     

Endotoxin, TLR4 signaling and vascular inflammation: potential therapeutic targets in cardiovascular disease

Cardiovascular disease ranks among the leading causes of morbidity and mortality in adult populations in the Western world. Significant progress in understanding the etiology of cardiovascular disease has come from recent recognition that chronic inflammation plays a key role in its development. The principal mediators of this inflammatory response, and the mechanisms by which they work, however, are incompletely understood. Moreover, the complex nature of the inflammatory response poses significant challenges to the development of effective and targeted treatments. Potentially promising targets to reduce inflammation in atherosclerosis include Toll-like receptor (TLR) pathways and anti-inflammatory factors that modulate TLR signaling. In this review, we outline studies that provide insight into the links between cardiovascular disease and inflammation, focusing on innate immunity and endotoxin/TLR4 signaling. We also discuss the contribution of specific host immune/inflammatory responses to atherogenesis, and describe cellular signaling pathways (lipopolysaccharide-binding protein [LBP], CD14, MD-2, TLR4, MyD88, and NF-kappaB, among others) that play key roles in innate immune signaling. Finally, we discuss the therapeutic potential of modulating these cellular signaling pathways as future strategies for the prevention and treatment of cardiovascular disease, including such approaches as specific targeting of the TLR4 signaling pathway, antibiotic therapy, drug classes with broad anti-inflammatory activity (statins, thiazolidinediones), and the potential of vaccine development. Because of the complexity of the links between low-level chronic infections, inflammation, and atherosclerosis, treatment and prevention of cardiovascular disease will likely require an integrated approach that utilizes a combination of these strategies to target the underlying inflammatory processes.     

Cytokines as therapeutic targets to reduce cardiovascular risk in chronic inflammation

Patients with chronic inflammatory diseases, such as rheumatoid arthritis (RA), systemic lupus erythematosus, psoriasis and Crohn's disease have an increased atherosclerotic risk which cannot be explained by traditional cardiovascular risk factors alone. Inflammatory pathways are implicated in this increased vascular risk. The involvement of cytokine-related signaling pathways in inflammatory diseases has prompted the development of many therapeutic strategies aimed at their modulation to limit disease severity and progression. Whether modulation of these pathways would similarly alter the inflammatory processes related to accelerated atherosclerosis remains unknown. In this review we will focus on the role of pro-inflammatory cytokines and their inhibitors in RA, and whether they may be causal in the accelerated atherosclerosis seen in these patients.     

Identification of new therapeutic targets for prevention of CNS inflammation

Multiple sclerosis (MS) is a disease of complex pathologies, which involves infiltration by CD4(+) and CD8(+) T cells of and response within the central nervous system. Expression in the CNS of cytokines, reactive nitrogen species and costimulator molecules have all been described in MS. Notably, the cytokines IFN-gamma and TNF are strongly expressed. Microglial cells in the CNS express costimulator molecules and it is assumed that they play a role in directing or inducing the T cell response. Transgenic experiments have tested the effects of overexpression of these molecules in mice and have shown that TNF has multiple effects in the CNS. These range from pro-inflammatory effects of soluble TNF signalling through one of its receptors TNF-RI, to protective/regenerative effects of membrane-associated TNF signalling through the other receptor, TNF-RII. Although IFN-gamma induces nitric oxide production via the enzyme inducible nitric oxide synthase, which is immunosuppressive, IFN-gamma is predominantly pro-inflammatory. In CNS disease in mice that involves CD8(+) T cells, IFN-gamma blockade is protective. Finally, microglial expression of the costimulator ligand B7.2 induces demyelinating pathology. Animal experiments therefore point to IFN-gamma and costimulatory microglia as logical targets of therapy for MS. IFN-gamma represents a more accessible target and should therefore be pursued at the earliest opportunity.     

NF-kappaB and inflammation in genetic disease

By responding to pro-inflammatory cytokines, such as IL-1beta and TNF-alpha, and controlling itself the expression of numerous mediators of inflammation, NF-kappaB plays a pivotal role in controlling the proper sequence of events characterizing the inflammation process. Although excessive NF-kappaB activation is often associated with inflammatory signs in many different tissues, impaired NF-kappaB activation can also generate inflammation. This is the case in humans suffering from the genetic disease incontinentia pigmenti that exhibit severe skin inflammation. Identifying the molecular basis of this pathology, mutations affecting the gene coding for NEMO, has allowed production of mouse models for investigating the disease. Their characterization supports the view that a very tight positive and negative regulation of the NF-kappaB signaling pathway is required in vivo to ensure not only a fine-tuned response to injury or infection but also to maintain tissue homeostasis.     

Molecular targets as therapeutic strategies in the management of breast cancer

Although the molecular and genetic determinants of most sporadic breast cancers remain unknown, increasing understanding of molecular and genetic events affecting breast carcinogenesis has provided information about the potential roles of specific biomarkers in tumour development and spread. It is now recognised that mutations of some tumour suppressor genes appear to play important early roles in the formation of some breast cancers. In addition, alterations in proto-oncogenes may contribute to the development of some breast cancers. The study of breast tumour biology at the molecular level has led to the development of targeted drug design, which provides a variety of agents targeted at specific molecules for the prevention, diagnosis and treatment of breast cancer. This review will describe the recognised molecular targets in breast cancer.