ReviewRedox signaling in macrophages
Introduction
The ability of cells to communicate with each other and to respond to their environment relies on biological mechanisms that allow the information to travel from the cell surface to the nucleus. These mechanisms referred to as signal transduction pathways have been extensively studied in the context of receptor–ligand interaction. Components of these pathways include second messengers, kinases, phospholipases, and phosphatases, among others. In recent years, it has become increasingly clear that ROS, such as superoxide (O2−) and hydrogen peroxide (H2O2) may act as second messengers. Observations made some twenty years ago had suggested that ROS may play a role in modulating cellular function. Studies done then revealed that exogenous H2O2 could mimic the action of the insulin growth factor (Czech, 1976). Shortly thereafter, insulin and nerve growth factor were shown to stimulate endogenous H2O2 production (Mukherjee et al., 1978, Mukherjee and Mukherjee, 1982). These interesting phenomena were overshadowed by studies concentrating on the role of ROS in the pathology of various diseases, the biochemistry of exogenous toxicants, and the killing of bacteria by phagocytes. The discovery of redox-sensitive transcription factors and that nitric oxide , a free radical produced enzymatically, plays a physiological role in vasodilatation and neurotransmission through activation of soluble guanylate cyclase (Gruetter et al., 1979) further supported the concept that ROS and reactive nitrogen species (RNS) can act as second messengers to modulate signaling pathways. This led to the renaissance of the field of redox signaling (Forman and Cadenas, 1997, Adler et al., 1999, Finkel, 1999, Suzuki et al., 1997, Thannickal and Fanburg, 2000, Ignarro, 2000) and with the accumulation of data in various systems, a clearer picture is emerging of the signaling pathways and specific targets affected by ROS/RNS. Here, we will briefly review some of the new concepts in redox signaling and summarize studies in the macrophage, a hematopoietic cell that plays an essential role in inflammation and has the capability to produce both ROS and RNS.
Section snippets
Oxidative stress vs. redox signaling
The effects of oxidants on signaling pathways are often characterized as resulting from oxidative stress. However, oxidative stress, defined as an imbalance between oxidant exposure and antioxidant protection, entails a range of responses that differ greatly with the type of stress and the sensitivity of the cells that are exposed to it. Severe oxidative stress is associated with threats to cell function and viability, resulting in activation of repair mechanisms or apoptosis and sometimes
Endogenous production of ROS/RNS
Initial studies of redox signaling were performed with exogenous oxidants, mostly added as a bolus. More recently, studies have concentrated on conditions that lead to endogenous production of ROS, although in this case, the amount and source of ROS generated are not always defined. Nitric oxide (, nitrogen monoxide) is enzymatically produced by nitric oxide synthases (NOS) through the oxidation of L-arginine by a five-electron oxidative reaction in the presence of oxygen and NADPH (Fig. 2).
ROS and RNS chemistry
As the reactive oxygen and nitrogen species are deemed as second messengers, it is important to discuss whether their properties qualify them as such. Second messengers have four basic characteristics that allow regulation. (1) They are either enzymatically generated or regulated by channels and pumps (2) They are enzymatically degraded. (3) Their concentration rises and falls within a short period, and (4) They are specific in action. In the following section, we will detail some of the
ROS/RNS detection
Determining whether any ROS or RNS are involved in a signaling pathway is made difficult by their fleeting existence and low concentrations, due to their reactivity and the remarkable catalytic capacity of the enzymes that specifically catabolize them. For example, SODs have rate constants near diffusion limitation and the steady-state concentration of O2− has been estimated to be ∼10−11 M. Thus, even a 100-fold transient increase in O2− would be difficult to observe. Furthermore, one cannot
ROS/RNS targets
Many studies in the literature have reported various effects by ROS/RNS on signaling pathways (for reviews see Allen and Tresini, 2000; Forman and Cadenas, 1997, Adler et al., 1999, Finkel, 1999, Suzuki et al., 1997, Thannickal and Fanburg, 2000, Ignarro, 2000). At first, an ambiguous picture of these processes emerged, attributable to several factors such as the great variability in dose and mode of administration of exogenous oxidants, and the diversity in cell types used. A lack of knowledge
Redox signaling in macrophages
The term “macrophage” encompasses different cell types of monocytic origin that acquire particular properties as a function of their environment. Studies regarding the role of oxidants on macrophage function have used both primary cells in humans and rodents and cell lines of various origins, often transformed or derived from tumors. Thus, caution must be exerted not to “generalize” the data, but instead to interpret them within the system used as many differences exist between cell populations
Conclusions
Evidence is accumulating in support of a signaling role for the reactive oxygen species produced by the respiratory burst. It is also important to remember that macrophages are long-lived cells with a less intense respiratory burst as those mounted by neutrophils or eosinophils. Although some studies have shown that ROS can interfere in some of the signaling pathways of neutrophils, this signaling role may not be similar in these cells, as neutrophils from patients with chronic granulomatous
Acknowledgements
As this is a brief review, we could not cite many of the important contributions to this rapidly growing field. Work from our laboratories was supported by a grant from the National Institutes of Health, HL37556 and ES05511. We thank Dr. Dale Dickinson for critical reading of the manuscript and our co-workers for their contributions.
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