Prostanoids as Regulators of Innate and Adaptive Immunity

Abstract

Potent, oxygenated lipid molecules called prostanoids regulate a wide variety of physiological responses and pathological processes. Prostanoids are produced by various cell types and act on target cells through specific G protein-coupled receptors. Although prostanoids have historically been considered acute inflammation mediators, studies using specific receptor knockout mice indicate that prostanoids, in fact, regulate various aspects of both innate and adaptive immunity. Each prostanoid, depending on which receptor it acts on, exerts specific effects on immune cells such as macrophages, dendritic cells, and T and B lymphocytes, often in concert with microbial ligands and cytokines, to affect the strength, quality, and duration of immune responses. Prostanoids are also relevant to immunopathology, from inflammation to autoimmunity and cancer. Here, we review the role of prostanoids in regulating immunity, their involvement in immunopathology, and areas of insight that may lead to new therapeutic opportunities.

Introduction

The immune response, a highly coordinated process involving an array of cell types, normally protects the body from pathogens while maintaining tolerance to self-antigens and harmless environmental antigens. This tightly regulated response occurs within a complex network of cell contact-dependent interactions and cellular signaling pathways mediated by a plethora of soluble factors. Although cytokines are critical soluble mediators that regulate the differentiation, maturation, and activation of various immune cells, a variety of endogenous agents are increasingly being recognized as modulators of immune reactivity, including chemokines, bioamines, purines, and lipid mediators such as prostanoids. Although prostanoids were recognized as being important in immune responses more than 35 years ago (Goodwin et al., 1977, Plescia et al., 1975), their potent influence on immune responses has recently gathered a greater deal of attention.

Prostanoids act in a wide variety of physiological responses and pathological processes. These potent oxygenated lipids are generated when unsaturated 20-carbon fatty acids such as arachidonic acid (AA) are metabolized through the cyclooxygenase (COX) pathway. Following cellular activation, AA is released from membrane phospholipids by phospholipase A₂ and is then converted to the prostaglandin (PG) intermediate PGH₂ by COX-1 and COX-2 (Smith & Langenbach, 2001). The COX isozymes catalyze a two-step reaction, first cyclizing AA to PGG₂ and then reducing the 15-hydroperoxy group to form PGH₂. Cell-specific PG synthases catalyze the conversion of PGH₂ to the five primary bioactive prostanoids PGD₂, PGE₂, PGF_2α, PGI₂, and thromboxane A₂ (TXA₂) (Fig. 5.1). The importance of this pathway in various diseases is underscored by the use of nonsteroidal anti-inflammatory drugs (NSAIDs), which inhibit prostanoid synthesis by inhibiting COX. Each prostanoid is generated in specific cells; in the immune system, the major prostanoid producers are cells involved in innate immune responses, such as macrophages and dendritic cells (DCs). Locally released prostanoids act as autacoids within the tissue via specific cell-surface receptors.

Prostanoid receptors, which were first characterized pharmacologically, are classified into five basic types DP, EP, FP, IP, and TP for the prostanoids PGD₂, PGE₂, PGF_2α, PGI₂, and TXA₂, respectively. EP has four subtypes, designated EP1, EP2, EP3, and EP4. Molecular identification of this family of eight prostanoid receptors revealed that their cDNAs encode seven-transmembrane G protein-coupled receptors (GPCRs), which couple to one or more signal-transduction pathways (Breyer et al., 2001, Coleman et al., 1994, Narumiya et al., 1999). In some animal species, EP1, EP3, FP, and TP have mRNA splice variants (Pierce & Regan, 1998). A second type of PGD₂ receptor, CRTH2 (chemoattractant receptor homologous molecule expressed by T helper 2 (Th2) cells), was identified by molecular analysis as belonging to the leukocyte chemoattractant receptor family (Nagata & Hirai, 2003). CRTH2 is also called DP2, referring to its endogenous ligand, with the first-identified DP receptor designated as DP1.

Prostanoids have historically been considered as acute inflammation mediators, causing symptoms such as fever, pain, and edema. The generation and study of specific receptor-deficient mice has clarified the functions mediated by each prostanoid acting on each receptor (Hirata and Narumiya, 2011, Narumiya, 2007, Narumiya and FitzGerald, 2001, Sugimoto and Narumiya, 2007, Woodward et al., 2011). Each receptor's role has also been studied using specific agonists and antagonists. These studies have revealed that prostanoids play much more fundamental roles in the normal physiology of many organ systems, including the cardiovascular, gastrointestinal, nervous, and immune systems, than had previously been thought. In the immune system, prostanoids have been found to influence many functions of those cells involved in innate and adaptive immune responses, including macrophages, DCs, natural killer (NK) cells, and T and B lymphocytes. Prostanoids are critically involved in immunopathological processes ranging from inflammation to allergic and autoimmune disorders.

This review begins with a synopsis of the general features and individual functions of prostanoid receptors and then focuses on the role of prostanoids and their receptors in innate and adaptive immunity. We will also discuss their role in immunopathology, and how the prostanoid pathway might be exploited therapeutically to control immunopathological conditions.