Associate editor: C.E. Müller
Adenosine 5′-triphosphate and adenosine as endogenous signaling molecules in immunity and inflammation

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Abstract

Human health is under constant threat of a wide variety of dangers, both self and nonself. The immune system is occupied with protecting the host against such dangers in order to preserve human health. For that purpose, the immune system is equipped with a diverse array of both cellular and non-cellular effectors that are in continuous communication with each other. The naturally occurring nucleotide adenosine 5′-triphosphate (ATP) and its metabolite adenosine (Ado) probably constitute an intrinsic part of this extensive immunological network through purinergic signaling by their cognate receptors, which are widely expressed throughout the body. This review provides a thorough overview of the effects of ATP and Ado on major immune cell types. The overwhelming evidence indicates that ATP and Ado are important endogenous signaling molecules in immunity and inflammation. Although the role of ATP and Ado during the course of inflammatory and immune responses in vivo appears to be extremely complex, we propose that their immunological role is both interdependent and multifaceted, meaning that the nature of their effects may shift from immunostimulatory to immunoregulatory or vice versa depending on extracellular concentrations as well as on expression patterns of purinergic receptors and ecto-enzymes. Purinergic signaling thus contributes to the fine-tuning of inflammatory and immune responses in such a way that the danger to the host is eliminated efficiently with minimal damage to healthy tissues.

Introduction

The naturally occurring nucleotide adenosine 5′-triphosphate (ATP) is normally present in every living cell of the human body and is well-known for its role in intracellular energy metabolism. In addition to this intracellular role, ATP in the extracellular compartment is thought to contribute to the regulation of a variety of other biological processes, including cardiac function, neurotransmission, muscle contraction, vasodilatation, bone metabolism, liver glycogen metabolism and inflammation (Agteresch et al., 1999, Hoebertz et al., 2003, Burnstock & Knight, 2004).

The human immune system comprises an interactive network of lymphoid organs and immune cells, and is essential to host defense (Delves & Roitt, 2000, Parkin & Cohen, 2001). Interaction between the various components of the immune system during activation is realized by multiple signaling molecules. These molecules, which can be released in response to tissue injury or exogenous pathogens, signal danger to the host and are necessary for initiating primary immune responses as well as for controlling the course and resolution of the concomitant inflammatory processes (Gallucci & Matzinger, 2001, Nathan, 2002, Gilroy et al., 2004, Rock et al., 2004, Skoberne et al., 2004). Extracellular nucleotides such as ATP may function as endogenous signaling molecules that control inflammation and immune responses (Di Virgilio et al., 2003, La Sala et al., 2003, Di Virgilio, 2005). Modulation of inflammatory processes and immune responses by extracellular ATP is complex and results from specific effects on a wide variety of both immune and non-immune cells.

ATP's role in immunity is closely related to one of its breakdown products, the nucleoside adenosine (Ado). Ado has an already established role in immunity (Cronstein, 1994, Montesinos & Cronstein, 2001, Ohta & Sitkovsky, 2001, Sullivan, 2003, Hasko & Cronstein, 2004, Lukashev et al., 2004, Sitkovsky et al., 2004, Lappas et al., 2005b, Lukashev et al., 2005), in which it may contribute to the engineering of inflammation and immune reponses by providing a suppressive tissue-protecting signal in a delayed, negative feedback manner (Gomez & Sitkovsky, 2003b, Sitkovsky, 2003, Sitkovsky & Ohta, 2005). The notion of an interrelation between ATP and Ado is firmly based on the presence of a large family of purinergic receptors (P1 and P2 receptors for Ado and ATP, respectively) that are mostly co-expressed by immune and non-immune cells. Several enzymes, which are also expressed by various immune and non-immune cells, are involved in a purinergic cascade by which extracellular purine levels and the ensuing purinergic signaling can be dynamically controlled during inflammatory and immune responses.

This review discusses the role of extracellular ATP and Ado in immunity and inflammation with special focus on their interplay.

Section snippets

Extracellular metabolism

Whereas intracellular concentrations of ATP are very high (3–10 mM), its extracellular concentrations are considerably lower. Physiological ATP concentrations in plasma are normally submicromolar (400–700 nM) (Coade & Pearson, 1989, Ryan et al., 1991, Ryan et al., 1996). Compared to ATP, plasma concentrations of Ado are usually about 10-fold lower (40–80 nM) (Harkness et al., 1983, Ontyd & Schrader, 1984, Yoneyama et al., 2004). However, extracellular concentrations of both ATP and Ado can rise

Purinergic receptors

A large family of membrane-bound receptors mediates cell signaling by ATP and Ado. These so-called purinergic receptors ultimately determine the variety of effects induced by extracellular ATP and Ado. Two families of purinergic receptors have been defined to date, namely P1 and P2 receptors (Table 1) (Ralevic & Burnstock, 1998). P1 receptors belong to the superfamily of seven transmembrane-spanning receptors which are subdivided into A1, A2A, A2B and A3 receptor subtypes (Ralevic & Burnstock,

Effects of ATP and adenosine on immune cell function

For insight in the role of ATP and Ado in immunity and inflammation, an overview of their effects on major cell types involved in innate and adaptive immunity is outlined in the following sections.

ATP and adenosine are endogenous signaling molecules in immunity and inflammation

The extensive available data on the immunologic effects of purinergic signaling by extracellular ATP and Ado, as presented in the previous paragraphs, gives overwhelming evidence that these endogenous signaling molecules and their purinergic receptors play a major role in immunity and inflammation. However, the presented data also suggest that the role of ATP and Ado in immunity and inflammation is extremely complex and interdependent. Existing knowledge derives mainly from in vitro studies,

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