Current Drug Targets - Inflammation & Allergy - Volume 2, Issue 3, 2003

Atopic disorders such as allergic rhinitis, asthma and atopic dermatitis are associated with skewing of immune responses towards a TH2 phenotype, resulting in eosinophilic inflammation. TH2 cytokines promote eosinophil growth, migration and activation, mast cell differentiation, and IgE production, and are candidate mediators of pathologic abnormalities in asthma and other atopic diseases. There has been a significant increase in the prevalence of allergic disorders over the past several decades. Recent epidemiological studies suggest that reduced early-life exposure to strong TH1 stimuli in industrialized counties has skewed the TH1 / TH2 balance towards TH2 responses. Improved hygiene, vaccination, and use of antibiotics may contribute to this imbalance. In the last half of the twentieth century we have seen the use of multiple agents to treat atopic disorders, ranging from antihistamines, steroids and leukotriene modifiers to anti-IgE antibodies. All these agents can block symptoms but do not significantly modify the course of the disease. Recent attempts to restore TH1 / TH2 balance by blocking TH2 cytokines or inducing TH1 cytokines, have not only failed to alter the outcome of atopic diseases but, in some cases, have caused significant adverse effects. An alternate method of suppressing TH2 responses takes advantage of the innate immune response to bacterial DNA. Oligodeoxynucleotides (ODN) containing sequence motifs centered on unmethylated CG dinucleotides (CpG ODN) resemble bacterial DNA, and like bacterial DNA are immunostimulatory; we and others have shown that CpG ODN can suppress TH2- mediated atopic inflammation without requiring the induction of TH1-type cytokines. These agents may represent a novel therapeutic approach toward restoring immune tolerance in atopic individuals

Matrix metalloproteinase 9 (MMP-9; gelatinase B) belongs to the subfamily of MMPs that play an important role in tissue remodelling in normal and pathological inflammatory processes. MMP-9 is a major secretion product of macrophages and a component of cytoplasmic granules of neutrophils. The enzyme is also secreted by lymphocytes and stromal cells upon stimulation by inflammatory cytokines, or upon delivery of bi-directional activation signals following integrin-mediated cell-cell or cell -extracellular matrix (ECM) contacts. Since the integrity of the tissue architecture is closely dependent of the delicate balance between MMPs and their inhibitors, excessive production of MMP-9 is linked to tissue damage and degenerative inflammatory disorders. As a consequence, regulation of gene transcription and tissue-specific expression of MMP-9 in normal and diseased states are being actively investigated to pave the way for new therapeutic targets. The objective of this article is to provide an overview of recent developments in the field of mmp-9 gene expression in different cell types, from the triggering of cell-surface receptors, to the activation of cytoplasmic mediators and transcription factors responsible for the activation of MMP-9 promoter. We will then focus on emerging evidence showing that transcription of mmp-9 gene can be controlled by epigenetic mechanisms. The usefulness of targeting the signalling pathways regulating MMP-9 expression for the treatment of inflammatory disorders and other indications will be discussed in light of these findings.

The mechanism of action of anti-rheumatic gold compounds on 12-Otetradecanoylphorbol 13-acetate (TPA)-induced prostaglandin E2 (PGE2) production in rat peritoneal macrophages were examined. Auranofin (AF) at 3-10 μM inhibited TPAinduced PGE2 production in a concentration-dependent manner. In the pharmacological experiments , prostaglandin G / H synthase (PGHS)-2-dependent PGE2 production was inhibited by 10 μM of AF. The enzyme activities of both PGHS-1 and PGHS-2 were not affected by the 10 μM AF. Other gold compounds, aurothioglucose (ATG) and aurothiomalate (ATM) did not inhibit PGE2 production at 10 μM. AF decreased the PGHS-2 protein content, but had no effect on the PGHS-1 protein content. AF at 3-10 μM decreased the PGHS-2 messenger RNA (mRNA) level by RT-PCR determination. Then, the effect of AF on nuclear factor kappa B (NF-κB), one of the transcription factors known to regulate transcription of a group of proinflammatory proteins, was determined. AF at 1-10 μM inhibited nuclear translocation of NF-κB in a concentration-dependent manner. ATG and ATM at 10 μM did not inhibit NF-κB nuclear translocation, but with 20 h preincubation, ATG and ATM inhibited PGE2 production and NF-κB nuclear translocation. AF, ATG, and ATM did not affect the binding of NF-κB to its specific DNA. These observations may suggest that the effects of gold compounds on the inhibition of NF-κB nuclear translocation plays one of the major role in its anti-inflammatory effects in rat peritoneal macrophages.

Antibacterial peptides function as effectors for defense in innate immunity. In mammals, they are implicated in the barrier protection of epithelia where their expression can be induced during infection and inflammation. Over a dozen of antibacterial peptides have been identified in humans. Among these, defensins and cathelicidins have been well characterized. Two types of defensins (α- and β-defensins) are recognized based on the presence of their conserved six cysteine residues, whereas cathelicidins are characterized by a homologous cathelin sequence in the pro-region and a variable antibacterial C-terminal sequence. Human β-defensins and cathelicidin hCAP18 / LL-37 are mainly expressed in epithelial tissues where mast cells are present. Here we review the structure of human β-defensins and cathelicidin, and describe their multiple activities on mast cells to induce chemotaxis, degranulation and prostaglandin D2 production, acting through receptors coupled to G-protein-phospholipase C pathway. Thus, in addition to their bactericidal activities, epithelial cell-derived antibacterial peptides may modulate the inflammatory responses by recruiting mast cells to inflammation foci and inducing the degranulation as well as prostaglandin production from this cell population.

Several lines of evidence have suggested that autoreactive antibodies (Abs) may be triggered by some endogenous antigen (Ag) and undergo affinity maturation toward the target through somatic mutation coupled with isotype switching. To understand the mechanism leading to pathogenic auto-Ab production, it is of great importance to analyze endogenous Ags that can break immunologic tolerance and reveal how the triggered auto-Abs evolve to acquire pathogenicity. As for the first issue, chemically modified self-proteins that are frequently found in inflamed tissues are potential candidates. These post-translational modifications might give rise to the generation of neoepitopes to which T- and B- lymphocytes are not tolerated. In the second part, it is discussed how auto-Abs thus triggered undergo affinity maturation toward target auto-Ags. Recently, not only immature B cells in the bone marrow, but also a population of peripheral B cells have been shown to undergo secondary V(D)J recombination of immunoglobulin genes, thereby changing the Ag-specificity. This process is termed receptor revision, which, along with somatic mutation, is considered to contribute to the formation of highaffinity Abs. Receptor revision and somatic mutation may generate auto-Abs if the deletion mechanism of autoreactive clones is impaired. B cells that had undergone receptor revision have been isolated from ectopic germinal centers in inflamed tissues in patients with rheumatoid arthritis. Investigations on the link between inflammation and autoimmunity will provide new aspects for therapeutic targets in the treatment of autoimmune diseases.

Myocardial infarction is associated with an inflammatory response, ultimately leading to healing and scar formation. Reperfused myocardial infarcts exhibit an enhanced inflammatory reaction, and are associated with improved cardiac repair and patient survival. This review summarizes our current knowledge of the inflammatory mechanisms mediating injury and repair following myocardial ischemia and reperfusion. Myocardial necrosis is associated with complement activation and free radical generation, triggering a cytokine cascade and chemokine upregulation. Interleukin (IL)-8 and C5a are released in the ischemic myocardium, and may have a crucial role in neutrophil recruitment. Extravasated neutrophils may induce potent cytotoxic effects through the release of proteolytic enzymes and the adhesion with Intercellular Adhesion Molecule (ICAM)-1 expressing cardiomyocytes. However, despite these potentially injurious effects, the postreperfusion inflammatory response may significantly enhance healing. Monocyte Chemoattractant Protein (MCP)-1 is induced in the infarcted area and may regulate mononuclear cell recruitment. Accumulation of monocyte-derived macrophages, and mast cells may increase expression of growth factors inducing angiogenesis and fibroblast accumulation in the infarct. In addition, expression of cytokines inhibiting the inflammatory response, such as Interleukin (IL)-10 may suppress injury. Matrix Metalloproteinases (MMPs) and their inhibitors regulate extracellular matrix deposition and play an important role in mediating ventricular remodeling. Inflammatory mediators may induce recruitment of blood-derived primitive stem cells in the healing infarct, which may differentiate into endothelial cells and even lead to limited myocardial regeneration. Understanding the cellular and molecular steps involved in regulating infarct healing may lead to specific interventions aimed at optimizing cardiac repair.

The designation of atherosclerosis as a chronic inflammatory process represents an interesting paradigmatic shift for cardiologists. The plasma concentrations of interleukin-6 and its hepatic byproduct, C-reactive protein, may reflect the intensity of occult plaque inflammation and the vulnerability to rupture. Monocyte chemoattractant protein-1 and interleukin-8 play a crucial role in initiating atherosclerosis by recruiting monocytes / macrophages to the vessel wall, which promotes atherosclerotic lesions and plaque vulnerability. In addition, circulating levels of these proinflammatory cytokines increase in patients with acute myocardial infarction and unstable angina, but not in those with stable angina. Also, the plasma concentrations of these cytokines increase after percutaneous coronary intervention, causing late restenosis after the procedure. Angiotensin II and other atherogenic factors induce these cytokines in the cardiovascular tissues through the activation of transcription factors, such as nuclear factor-κB or peroxisome proliferatoractivated receptors. Conversely, HMG-CoA reductase inhibitors (statins) can potently inhibit these proinflammatory factors in the vessels. A small GTP-binding protein, Rho, may be a key molecule to explain the anti-inflammatory effects of statins. Interleukin-10 also exerts anti-inflammatory effects on the cardiovascular tissues, possibly by deactivating proinflammatory cytokines and inducible nitric oxide synthase. Gene therapy using interleukin-10 may be a promising means for untreatable or complicated cases of cardiovascular diseases. Thus, therapeutic modulations of these inflammatory cytokines may be useful in the prevention of atherosclerosis and future cardiovascular events.