Corticosteroids are broad-spectrum anti-inflammatory agents that reduce the transcription of genes encoding COX-2, phospholipase A2, proinflammatory cytokines (e.g., IL-1 and TNF), and iNOS.
Leukotriene receptor antagonists block leukotriene receptors and prevent the actions of the leukotrienes. These drugs (e.g., Montelukast) are useful in the treatment of asthma.
Cytokines are proteins secreted by many cell types (principally activated lymphocytes, macrophages, and dendritic cells, but also endothelial, epithelial, and connective tissue cells) that mediate and regulate immune and inflammatory reactions. By convention, growth factors that act on epithelial and mesenchymal cells are not grouped under cytokines. The general properties and functions of cytokines are discussed in Chapter 5. Here the cytokines involved in acute inflammation are reviewed (
Table 3.7
TNF and IL-1 serve critical roles in leukocyte recruitment by promoting adhesion of leukocytes to endothelium and their migration through vessels. Activated macrophages and dendritic cells mainly produce these cytokines; TNF also is produced by T lymphocytes and mast cells, and some epithelial cells produce IL-1 as well. Microbial products, foreign bodies, necrotic cells, and a variety of other inflammatory stimuli can stimulate the secretion of TNF and IL-1. The production of TNF is induced by signals through TLRs and other microbial sensors, and the synthesis of IL-1 is stimulated by the same signals, but the generation of the biologically active form of this cytokine is dependent on the inflammasome, described earlier.
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IL-6 Macrophages, Systemic effects (acute phase other cells response)
IL-17 T lymphocytes Recruitment of neutrophils and monocytes
IL-17 T lymphocytes Recruitment of neutrophils and monocytes
The most important cytokines involved in inflammatory reactions are listed. Many other cytokines may play lesser roles in inflammation.There is also considerable overlap between the cytokines involved in acute and chronic inflammation. Specifically, all the cytokines listed under acute inflammation may also contribute to chronic inflammatory reactions. IFN-γ, Interferon-γ; IL-1, interleukin-1; NK, natural killer; TNF, tumor necrosis factor.
The actions of TNF and IL-1 contribute to the local and systemic reactions of inflammation (
Fig. 3.10 ). The most important roles of these cytokines in inflammation are the following:
Endothelial activation. Both TNF and IL-1 act on endothelium to induce a spectrum of changes referred to as endothelial activation. These changes include increased expression of endothelial adhesion molecules, mostly Eand P-selectins and ligands for leukocyte integrins; increased production of various mediators, including other cytokines and chemokines, and eicosanoids; and increased procoagulant activity of the endothelium.
Activation of leukocytes and other cells. TNF augments responses of neutrophils to other stimuli such as bacterial endotoxin and stimulates the microbicidal activity of macrophages. IL-1 activates fibroblasts to synthesize collagen and stimulates proliferation of synovial cells and other mesenchymal cells. IL-1 and IL-6 also stimulate the generation of a subset of CD4+ helper T cells called TH17 cells, described later and in Chapter 5.
Systemic acute-phase response. IL-1 and TNF (as well as IL-6) induce the systemic acute-phase responses associated with infection or injury, including fever (described later in the chapter). They also are implicated in the pathogenesis of the systemic inflammatory response syndrome (SIRS), resulting from disseminated bacterial infection (sepsis) and other serious conditions, described later.