Trends in Molecular Medicine
ReviewArachidonic-acid-derived eicosanoids: roles in biology and immunopathology
Introduction
Eicosanoids, including prostaglandins (PGs), leukotrienes (LTs) and lipoxins (LXs), are signalling molecules that are generated primarily through an oxidative pathway from arachidonic acid (AA) (Figure 1) but also from pathways originating from eicosapentaenoic and dihomo-γ-linolenic acids 1, 2, 3. AA-derived eicosanoids exert complex control over a wide range of physiological processes (Table 1). Many important aspects of immunity, such as cytokine production, antibody formation, differentiation, cell proliferation, migration and antigen presentation, are regulated by eicosanoids. Cells of the innate immune system, including tissue macrophages, sentinel dendritic cells (DCs) and neutrophils, are major producers of eicosanoids, which act locally at nanomolar concentrations on target cells. They exert their effects in an autocrine and paracrine fashion and affect the function of neighbouring cells. It has become increasingly apparent that eicosanoids and their receptors cooperate with other signalling molecules, particularly cytokines and chemokines, and have a crucial role in modulating physiological processes in both homeostatic and inflammatory conditions (Box 1).
Eicosanoid production is considerably increased during inflammation, and their biosynthetic pathways are of particular clinical relevance because their products are involved in the pathogenesis of various pathologies related to immune functions 4, 5, 6. A variety of therapeutic strategies based on eicosanoids and their receptors are currently being used, and others are on the horizon. However, pharmacological inhibition of eicosanoid biosynthesis might simultaneously be beneficial and deleterious. This review highlights recent developments in eicosanoid biology and immunopathology. We will discuss the major properties of AA-derived eicosanoids and their expanding roles in health and disease, focusing on the involvement of PGs, LTs and LXs in inflammation, cancer, autoimmunity and allergic diseases.
Section snippets
Eicosanoid biosynthesis from arachidonic acid
The biosynthesis of eicosanoids depends on the availability of free AA. When tissues are exposed to diverse physiological and pathological stimuli, such as growth factors, hormones or cytokines, AA is produced from membrane phospholipids by the action of phospholipase A2 (PLA2) enzymes and can then be converted into different eicosanoids. AA can be enzymatically metabolized by three main pathways: P-450 epoxygenase, cyclooxygenases (COXs) and lipoxygenases (LOXs) (Figure 1). The P-450
Eicosanoid receptors and signalling
Eicosanoids exert their effects by binding to membrane receptors. This can trigger an increase or decrease in the rate of cytosolic second messenger generation (cAMP or Ca2+), activation of a specific protein kinase or a change in membrane potential. We will focus here on PG and LT signalling because of their importance in the pathogenesis of several immunological and inflammatory diseases.
Endogenously produced PGs can undergo facilitated transport from the cell through known prostanoid
Eicosanoids and immune cells: production and immunomodulation
Eicosanoid synthetic profiles differ from one cell type to another. Among the cells involved in the immune response, macrophages are important producers of eicosanoids [17]. They are able to synthesize PGs as well as LTs. Resting macrophages exhibit COX and LOX activities, and cell stimulation activates both pathways. In vitro, many stimuli, including calcium ionophore, zymosan and immune complex, increase eicosanoid production. Mast cells are also able to produce eicosanoids, such as PGD2,
Eicosanoids and immunopathology
AA-derived eicosanoids seem to have important roles in immunopathology and have been implicated in inflammation, autoimmunity, allergic diseases and cancer. Examples of diseases in which pathogenesis involve eicosanoids are summarized in Table 2.
Targeting eicosanoids
Both COX and LOX pathways are of particular clinical relevance (Table 2). The COX pathway is the major target for non-steroidal anti-inflammatory drugs (NSAIDs), the most popular medications used to treat pain, fever and inflammation. NSAIDs inhibit the production of primary prostanoids by blocking the active site of COXs. Although their anti-inflammatory effects are well known, their long-term use is associated with gastrointestinal (GI) complications, such as ulceration [93]. For this reason,
Concluding remarks
The biological effects of eicosanoids are particularly important in immunity and inflammation. The roles of eicosanoids in biology and pathology are diverse and complex. This diversity is due to their variety in composition, targets and GPCR signalling. Further understanding of eicosanoid biology will be important for understanding the organ-specific effects of these unique compounds in health and disease. Several outstanding questions in this field are listed in Box 3.
Mice deficient in each of
Acknowledgements
We thank all members of our department and all collaborators on eicosanoid study.
Glossary
- Antigen-presenting cells (APCs)
- a functionally defined group of cells that are able to take up antigens and present them to T lymphocytes to stimulate immune responses. APCs include macrophages, endothelial cells, dendritic cells (DCs), Langerhans cells and B cells. DCs are considered ‘professional’ APCs because they are able to stimulate naïve T cells.
- Eicosanoids
- (from the Greek eikosi for ‘twenty’) are members of a family of oxygenated metabolites mainly synthesized from the 20-carbon fatty
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