Endocrine, Metabolic & Immune Disorders-Drug Targets (Formerly Current Drug Targets - Immune, Endocrine & Metabolic Disorders) - Volume 8, Issue 4, 2008

Human C-reactive protein (CRP), injected intravenously into mice or produced inside mice by a human transgene, protects mice from death following administration of lethal numbers of Streptococcus pneumoniae. The protective effect of CRP is due to reduction in the concentration of bacteria in the blood. The exact mechanism of CRP-dependent killing of pneumococci and the partners of CRP in this process are yet to be defined. The current efforts to determine the mechanism of action of CRP in mice are directed by four known in vitro functions of CRP: 1. the ability of pneumococcal C-polysaccharide-complexed CRP to activate complement pathways, 2. the ability of CRP to bind to Fcγ receptors on phagocytic cells, 3. the ability of CRP to bind to immobilized complement regulator protein factor H which can also be present on pneumococci, and, 4. the ability of CRP to interact with dendritic cells. CRP-treated dendritic cells may well be as host-defensive as CRP alone. An interesting condition for the protective function of CRP is that CRP must be given to mice within a few hours of the administration of pneumococci. CRP does not protect mice if given later, suggesting that CRP works prophylactically but not as a treatment for infection. However, full knowledge of CRP may lead to the development of CRP-based treatment strategies to control pneumococcal infection. Also, because CRP deficiency in humans has not yet been reported, it becomes important to investigate the deficiency of the mechanism of action of CRP in CRP-positive individuals.

Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a serine protease that belongs to the proprotein convertase family. PCSK9 is synthesized as a zymogen and its prodomain is cleaved by its own catalytic activity. The cleaved prodomain forms a protein complex with the rest of the PCSK9 carboxyl terminus within the endoplasmic reticulum and is secreted. Secreted PCSK9 has been shown to be able to reduce low-density lipoprotein receptor (LDLR) levels in vitro and in vivo. Thus PCSK9 has emerged as an important player modulating LDLR levels and plasma LDL cholesterol. Furthermore, PCSK9 deficiency leads to significantly lowered LDL cholesterol levels in humans and provides dramatic protection against coronary heart disease. We review here the current understanding of PCSK9 and its potential as a therapeutic target through which to reduce LDL cholesterol for prevention and treatment of coronary heart disease.

Investigations into the role of the adenosine A2b receptor have been enigmatic due to the lack of good selective high affinity agonists and antagonists. Over the last few years several new antagonist compounds, based either on a xanthine or pyrrolpyrimidine (polyheterocyclic) structure have been designed and these have been used to localise A2b receptors in different tissues and to determine their function. Recently, animals harbouring either a loss or an over-expression of the A2b receptor have been created and these suggest an anti-inflammatory role for the receptor. In this short review, we describe how the A2b receptor influences inflammation in different tissues. In the anterior pituitary gland the A2b receptors exist predominantly in folliculostellate cells where it stimulates secretion of IL-6 and VEGF and influences gapjunctional communication via connexin-43. The A2b receptor also mediates the release of pro-inflammatory cytokines from many tissues such as bronchial smooth muscle, intestinal epithelial cells and mast cells. The presence of a HIF-1α binding site in the promoter region of the A2b receptor gene shows that it is strongly implicated in hypoxia and angiogenesis. Targeting the A2b receptor may also be useful in combating autoimmune type I diabetes. These findings, together, indicate that the A2b receptor plays a role in inflammation; its precise action, whether pro- or anti-inflammatory however may be cell type dependent. Nevertheless several A2b receptor antagonists are being developed for therapeutic intervention and these are either at the preclinical stage or in phase I clinical trials as is the case for CVT-6883 for asthma.

Neovascularization (NV) of the normally avascular cornea arises from various causes including inflammation, infection, trauma, and contact lens wear. Corneal NV, whatever the cause, impairs vision and threatens the survival of corneal allografts, thus representing a serious clinical problem for which treatment is limited. Recent interest has focused on vascular endothelial growth factor (VEGF), a key angiogenic factor whose role in corneal NV is amply documented. While experimental studies underscore the efficacy of anti-VEGF targeted agents, there exists no clear consensus on the ideal treatment for this multifaceted pathology. This review discusses the therapeutic potential of CD36, a well established anti-angiogenic receptor. We present evidence that CD36 contributes significantly to the maintenance of corneal avascularity wherein its deficiency leads to age-related corneal NV. Data further reveal that activation of CD36 substantially attenuates and induces regression of inflammatory corneal NV via concerted inhibition of VEGFA, c-Jun N terminal kinase- 1, and c-Jun. In parallel studies, we demonstrate that hypoxia, a fundamental stimulus of NV, markedly elevates CD36 corneal expression in a hypoxia-inducible factor-1 and reactive oxygen species dependent manner. Collectively, our findings unveil interesting avenues for future research on the involvement of CD36 in neovascular eye disease and suggest CD36 agonists as potential therapeutic agents for the management of corneal NV, possibly in combination with anti- VEGF therapies.

Src kinase plays a key role in multiple signalling pathways regulating diverse cell functions from proliferation and survival to invasion and angiogenesis. In breast cancer, both Src protein levels and kinase activity are frequently elevated and its important role in these oncogenic processes make it a potential target for therapeutic intervention. Importantly, recent evidence has revealed a role for Src in mediating anti-hormone action and in acquired endocrine resistance. A number of small molecule inhibitors of Src kinase have been developed with preclinical data demonstrating their effectiveness at suppressing breast cancer growth and invasion in vitro whilst inhibiting disease spread in vivo. Significantly, there appears to be added benefit when these agents are given in combination with anti-oestrogens. These new findings suggest that Src inhibitors might have therapeutic value in breast cancer patients.

Activation of T lymphocytes through TCR signalling takes place within the context of numerous other cell surface proteins. To prevent unnecessary activation of T cells the immune system has developed an intricate balance between positive and negative costimulatory signals. Positive costimulatory signals determine whether antigen recognition by T cells leads to full activation or to anergy/death. In contrast, the expression of negative costimulatory molecules by T cells such as cytotoxic T lymphocyte antigen 4 (CTLA-4) mediates the regulation of an immune response and thus plays a pivotal role in the maintenance of peripheral tolerance. The new members of the CD28 family members, programmed death- 1 (PD-1) and B and T lymphocyte attenuator (BTLA) are expressed more broadly on various immune cells and are also induced upon inflammation. There is increasing evidence that negative costimulators are critically involved in the regulation of immune responses against parasitic infections. The production of pro-inflammatory cytokines is often required to control parasites but the same cytokines contribute to immunopathology. Recent studies indicate that these negative costimulators are not redundant but fulfil specific functions in different tissues. This might represent a means to provoke a fine-tuning of the immune response and to define tissue specific limits of inflammation that ensure proper physiological function of the respective organ. Thus, negative costimulators represent possible drug targets since their blockade leads to an increased immune response whereas their ligation dampens T cell activation and thereby might prevent immunopathology. This review examines the role of negative costimulators during parasitic infections, and we also discuss their therapeutic potential.

It has long been recognized that vitamin A and its metabolites have immune-regulatory roles but the mechanism has been unclear. Recently, there has been a significant progress in elucidating the functions of retinoic acid in regulation of immune cell development. Retinoic acid (all-trans and 9-cis retinoic acid) is produced from the cells of the intestine such as dendritic cells and provides an intestine-specific environmental cue to differentiating immune cells. When T cells and B cells are activated in the intestine and associated-lymphoid tissues, gut homing receptors are induced on the cells in a retinoic acid and antigen-dependent manner. Retinoic acid, produced by gut dendritic cells, is also an important signal that induces IgA-producing B cells. The gut homing T cells and B cells play essential roles in protecting the digestive tract from pathogens. Retinoic acid is required also for production of mature phagocytes in bone marrow. On the other hand, retinoic acid induces a subset of FoxP³⁺ regulatory T cells which is important for maintaining immune tolerance in the gut. Therefore, retinoids provide both positive and negative regulatory signals to fine-control the mucosal immune system.

Crohn's disease and Ulcerative Colitis, collectively termed inflammatory bowel disease (IBD), are chronic inflammatory disorders of the bowel. It is generally accepted that the pathology associated with IBD is characterized by a hyper-reactive immune response in the gut wall directed against the commensal intestinal bacterial flora, and that the CD4+ T cells dominate the adaptive immune response. Chemokines are small proteins involved in the guidance of migration of immune cells during normal homeostasis and inflammation. Chemokines have been shown to play a central role in recruiting inflammatory cells to the inflamed bowel of IBD patients, making the chemokine/receptor system appealing as new therapeutic targets to sustain remission in these patients. In the severe combined immunodeficiency transfer model of colitis, which histopathologically resembles human IBD, low numbers of CD4+CD25- T cells from congenic normal mice are transplanted into immune deficient mice, which in turn develop a chronic lethal colitis within 1-2 months. By simultaneous transplantation of CD4+CD25+ regulatory T cells (Tregs) it is possible to hinder development of colitis. Thus the model is well suited for studying mechanisms underling both the effector and the regulatory components of chronic inflammation. In the current review we discuss new possible targets for immune therapy in colitis.

Non alcoholic fatty liver disease (NAFLD) is defined as fat accumulation exceeding 5% to 10% by the weight of the liver, in the absence of other causes of steatosis. NAFLD is strongly associated with metabolic diseases, such as metabolic syndrome. At present, insulin resistance, elevated concentrations of free fatty acids and oxidants, and an imbalance between different cytokines have been identified as the common pathophysiological elements underlying both NAFLD and metabolic syndrome. Emerging evidence also considers NAFLD as the hepatic manifestation of metabolic syndrome and supports a possible direct role of fat liver in cardiovascular risk assessment. Further investigations are needed to better understand the role of NAFLD, as an independent active factor in metabolic syndrome and associated cardiovascular disease.

Systemic hypertension, a pathological process to which the renin-angiotensin system contributes importantly, is characterized by a thrombophilic diathesis and an increased risk for acute ischemic coronary events. That apparently contradictory profile might, to some extent, relate to the modulating properties of Angiotensin II, the effector arm of the renin angiotensin system, on tissue factor expression, the physiologic initiator of blood coagulation and a basic mechanism in the pathogenesis of acute thrombosis. In fact, monocytes and macrophages within the atherosclerotic plaque as well as inflamed vascular endothelial cells may locally synthesize Angiotensin II. In turn, the peptide, by binding to its specific membrane receptors, activates a series of intracellular signals eventually converging upon NF-κB, a transcription factor that upregulates tissue factor expression. Drugs interfering with the renin-angiotensin system, either by inhibiting conversion of Angiotensin I to Angiotensin II or by blocking its receptors, have the potential to inhibit tissue factor expression and to modulate its procoagulant effect. This property may contribute to the protection exerted by renin-angiotensin blockers from acute ischemic events in patients with hypertension and other cardiovascular diseases.