Mediators may be produced locally by cells at the site of inflammation, or may be derived from circulating inactive precursors that are activated at the site of inflammation. Cell-derived mediators are rapidly released from intracellular granules (e.g., amines) or are synthesized de novo (e.g., prostaglandins, leukotrienes, cytokines) in response to a stimulus. The major cell types that produce mediators of acute inflammation are tissue macrophages, dendritic cells, and mast cells, but platelets, neutrophils, endothelial cells, and most epithelia also can be induced to elaborate some of the mediators. Therefore, cell-derived mediators are most important for reactions against offending agents in tissues. Plasma-derived mediators (e.g., complement proteins) are present in the circulation as inactive precursors that must be activated, usually by a series of proteolytic cleavages, to acquire their biologic properties. They are produced mainly in the liver, are effective against circulating microbes, and also can be recruited into tissues.
Active mediators are produced only in response to various molecules that stimulate inflammation, including microbial products and substances released from necrotic cells. Many of these stimuli trigger well-defined receptors and signaling pathways, as described earlier. The usual requirement for microbes or dead tissues as the initiating stimulus ensures that inflammation is normally triggered only when and where it is needed.
Most of the mediators are short-lived. They quickly decay, or are inactivated by enzymes, or they are otherwise scavenged or inhibited. There is thus a system of checks and balances that regulates mediator actions. These built-in control mechanisms are discussed with each class of mediator.
One mediator can stimulate the release of other mediators. For instance, products of complement activation stimulate the release of histamine, and the cytokine TNF acts on endothelial cells to stimulate the production of another cytokine, IL-1, and many chemokines. The secondary mediators may have the same actions as the initial mediators but also may have different and even opposing activities, thus providing mechanisms for amplifying—or, in certain instances, counteracting—the initial action of a mediator.
Vasoactive Amines: Histamine and Serotonin
The two major vasoactive amines, so named because they have important actions on blood vessels, are histamine and serotonin. They are stored as preformed molecules in cells and are therefore among the first mediators to be released during inflammation. The richest sources of histamine are mast cells, which are normally present in the connective tissue adjacent to blood vessels. Histamine also is found in blood basophils and platelets. It is stored in mast cell granules and is released by degranulation in response to a variety of stimuli, including (1) physical injury, such as trauma, cold, or heat, by unknown mechanisms; (2) binding of antibodies to mast cells, which underlies immediate hypersensitivity (allergic) reactions (Chapter 5); and (3) products of complement called anaphylatoxins (C3a and C5a), described later. Antibodies and complement products bind to specific receptors on mast cells and trigger signaling pathways that induce rapid degranulation. Neuropeptides (e.g., substance P) and cytokines (IL-1, IL-8) also may trigger release of histamine.