Inflammatory mediators often play important roles in the normal cell, regulating the synthesis and turnover of ECM, for ex- ample. Accordingly, blocking their production can have adverse effects on normal cell physiology. At best, inflammation can be controlled by modulating the production of these mediators.

Eicosanoids

Arachidonic acid is produced by cleavage of a membrane-bound phospholipid, which sets into motion the arachidonic acid cascade and synthesis of many different carbon fatty acid derivatives. The cascade includes two prin- cipal arms: (1) the cyclooxygenase pathway, which leads to production of prostaglandins and thromboxanes, and (2) the lipoxygenase pathway, which produces leukotrienes and lipoxins. These compounds have varying ef- fects. Some, such as leukotriene B4 (LTB4) and prostaglandin E2 (PGE2), can stimulate cell infiltration (and thus be considered proinflammatory). Others such as lipoxin A4 can inhibit cell recruitment (and thus be con- sidered anti-inflammatory).

While many prostaglandins are inflammatory mediators, the one that plays a pivotal role in inflammation, and consequently has been studied in greatest depth, is PGE2. This eicosanoid is found at elevated levels in the synovial fluid of inflamed joints and mediates the edema associated with joint inflammation. Results of recent studies de- scribe both proinflammatory and anti- inflammatory roles for PGE2: it interacts with LTB4 to recruit cells, and it activates lipoxin A4 to resolve inflammation.

Cytokines

Interleukins

The interleukins are a class of low molecular weight proteins that modulate cell activity and regulate the immune system. Some interleukins are synthesized preferentially by certain cell types, while others appear to be produced by a wide variety of cells. For instance, IL-2 is released by T cells almost exclusively, whereas IL-1 is produced by macrophages, fibroblasts, and lymphocytes. Even tissue-specific cells, such as chondrocytes, can produce IL-1. At least 19 interleukins have been identified, and each has a specific role in cell and tissue maintenance.11-14 While the mechanisms of action of each of the interleukins are still being investigated, it is clear that they are the regulators of the immune system (Tables 1 and 2). Because of their roles in cartilage and bone metabolism, IL-1 and IL-6 are of particular interest to musculoskeletal medicine. IL-1 has been shown to both decrease synthesis and increase degradation of cartilage ECM components, and IL-1 and IL-6 stimulate the differentiation and recruitment of osteoclasts, the cells responsible for bone resorption.

Tumor Necrosis Factor-α
This cytokine derives its name from its ability to lyse tumors. Its name may be mislead- ing because TNF-α has been shown to have a much broader range of activity: it plays a major role in inflammation and in the immune response.12,13 As it appears early in the inflammation cascade, TNF-α is considered a possible initiator of further cytokine activity. Increased TNF-α induces and augments IL-1 activity; inhibitors of TNF-α de- crease IL-1 activity. For this reason, TNF-α has become the target cytokine for treatment of chronic inflammatory diseases. Several approaches to decrease production of this cytokine are currently being investigated.

Growth Factors

Several growth factors participate in the inflammatory process and in the degradative stages of arthritis. Vascular endothelial growth factor and basic fibroblast growth factor are two important agents; both stimulate endothelial proliferation and increase vascular permeability and angiogenesis.15,16 Both factors are produced by fibroblasts and macrophages in the vicinity of blood vessels and capillaries within the inflamed tissue.