Markers and Mediators of Inflammation
Following is a list of some of the most prominent markers of inflammation used in research and diagnosis. Some can be detected by blood tests (see “Diagnosis and Conventional Treatment of Chronic Inflammation”):
Tumor Necrosis Factor-alpha
Tumor necrosis factor-alpha (TNF-α) is an intercellular signaling protein called a cytokine, which can be released by multiple types of immune cells in response to cellular damage, stress, or infection. Originally identified as an anti-tumor compound produced by macrophages (immune cells),22 TNF-α is required for proper immune surveillance and function. Acting alone or with other inflammatory mediators, TNF-α slows the growth of many pathogens. It activates the bactericidal effects of neutrophils, and is required for the replication of several other immune cell types.23 Excessive TNF-α, however, can lead to a chronic inflammatory state, can increase thrombosis (blood clotting) and decrease cardiac contractility, and may be implicated in tumor initiation and promotion.7
Nuclear Factor Kappa-B
Nuclear factor kappa-B (NF-κB)is important in the initiation of the inflammatory response. When cells are exposed to damage signals (such as TNF-α or oxidative stress), they activate NF-κB, which turns on the expression of over 400 genes involved in the inflammatory response.23 These include other inflammatory cytokines, and pro-inflammatory enzymes including cyclooxygenase-2 (COX-2) and lipoxygenase. COX-2 is the enzyme responsible for synthesizing pro-inflammatory prostaglandins, and is the target of non-steroidal anti-inflammatory drugs (NSAIDs) (ibuprofen, aspirin) and COX-2 inhibitors (Celebrex).
Interleukins are cytokines that have many functions in the promotion and resolution of inflammation. Pro-inflammatory interleukins that have been the subject of most research include IL-1β, IL-6, and IL-8. IL-1β helps immune cells to move out of blood vessels and into damaged or dysfunctional tissues. IL-6 has both pro-inflammatory and anti-inflammatory roles, and coordinates the production of compounds required during the progression and resolution of acute inflammation. IL-8 is expressed by both immune and non-immune cells, and helps to attract neutrophils (immune cells that can destroy pathogens) to sites of injury.
C-reactive protein (CRP) is an acute-phase protein, one of several proteins rapidly produced by the liver during an inflammatory response. Its primary goal in acute inflammation is to coat damaged cells to make them easier to recognize by other immune cells.24 CRP elevation above basal levels is not diagnostic on its own, as it can raise in several cancers, rheumatologic, gastrointestinal, and cardiovascular conditions, and infections.25 Elevation of CRP (as determined by a high-sensitivity CRP assay or hs-CRP) has a strong association with elevated risk of cardiovascular disease and stroke.26
The cytokine factors mentioned earlier (interleukins, TNF-α) are “long-distance messages.” They are produced by cells at the site of inflammation and released into the blood, carrying information about the inflammatory response throughout the body. In contrast, eicosanoids are “local” messages; they are produced by cells that are proximal to the site of inflammation, and are meant to travel short distances (locally within the same organ, to neighboring cells, or sometimes only to different parts of the same cell) in order to elicit immune defenses.27 There are several families of eicosanoids (including prostaglandins, prostacyclins, leukotrienes, and thromboxanes) that are created by most cell types in all major organ systems. Aside from their roles in inflammation (and anti-inflammation), prostaglandins have a variety of functions in cell growth, kidney function, digestion, and the constriction and dilation of blood vessels. Thromboxanes are important mediators of the blood clotting process. Pro-inflammatory leukotrienes are important for recruiting and activating white blood cells during inflammation, and are best studied for their role in airway constriction and anaphylaxis.
Cells produce eicosanoids using unsaturated fatty acids that are part of their cell membranes. The fatty acid starting materials for eicosanoid synthesis are the essential fatty acids linoleic acid (omega-6) and its derivative arachidonic acid (AA); and alpha-linolenic acid (an omega-3) and its derivatives eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA). While generalizations about roles of these fatty acids in eicosanoid synthesis should be approached cautiously, the most potent inflammatory eicosanoids are produced from omega-6 fatty acids (linoleic and arachidonic acids). Diets high in omega-3 fatty acids are associated with lower biomarkers of inflammation and cardiovascular disease risk; proposed mechanisms include the production of less inflammatory or anti-inflammatory eicosanoids and through the cyclooxygenase and lipoxygenase enzymes.28
Cyclooxygenases and Lipoxygenases
The eicosanoids require several enzymatic steps to be synthesized from unsaturated fatty acids; the cyclooxygenase (COX) and lipoxygenase (LOX) enzymes catalyze the first steps in these reactions. Cyclooxygenases initiate the conversion of omega-3 and omega-6 derivatives into one of the many prostaglandins or thromboxanes. The interest in COX enzyme metabolism comes from the fact that its inhibition leads to decreased prostaglandin synthesis, and therefore a reduction in inflammation, fever, and pain. The analgesic and anti-inflammatory activity of aspirin and NSAIDs (like ibuprofen and naproxen) is due to their inhibition of COX enzymes. There are two COX enzymes with well-defined roles in humans (COX-1 and COX-2). COX-2 has the most relevance to the inflammatory process; it is normally inactive, but is turned on during inflammation and stimulates this process of inflammation by creating pro-inflammatory prostaglandins and thromboxanes.
Lipoxygenases convert fatty acids into proinflammatory leukotrienes, important local mediators of inflammation. Several potent inflammatory leukotrienes are produced by 5-LOX in mammals. Lipoxygenase enzymes, and the pro-inflammatory factors they produce, have a fundamental role in the inflammatory process by aiding in the recruitment of white blood cells to the site of inflammation. They also stimulate local cells to produce cytokines, which amplifies the inflammatory response.27 Thus, LOX enzymes may be involved in a wide variety of inflammatory conditions, and represent an additional target for anti-inflammatory therapy.
While COX and LOX enzymes are most often associated with pro-inflammatory processes, it is important to remember that both enzymes also produce factors that inhibit or resolve inflammation and promote tissue repair (including the prostacyclins and lipoxins). The proper transition from pro- to anti-inflammatory activities of the COX and LOX enzymes is important for the progression of a healthy inflammatory response.