Biologic Agents to Control Autoimmune Inflammation


TNF Inhibition

The study of RA has led much to our understanding regarding the role of TNF inhibition and treatment of rheumatic disease. It has served as the prototype for understanding the pathophysiology of immune-mediated inflammation [2]. Though TNF inhibition has been the primary clinical focus for the treatment of rheumatoid arthritis, further investigation has uncovered more information regarding the pathogenesis of RA and associated cytokine biology. In a review by Tracey et al., TNF was referred to as the “sentinel cytokine.” At low levels TNF is thought to aid in host defenses against infections. However, at high levels TNF can lead to increased inflammation and organ injury. In disease states TNF is considered to be pro-inflammatory [3]. It has been shown that TNF increases interleukin-1 (IL-1) a known pro-inflammatory cytokine in the synovial fluid of rheumatoid arthritis patients [1]. The role of IL-1 and autoimmune inflammation will be discussed later in the chapter. The expression of TNF is increased in immune-mediated inflammatory disease as a result of a failure of tolerance to self by both innate and adaptive immune cells, particularly T cells. As a result of increased expression, many other inflammatory cytokines are subsequently induced. The following figure is representative of the complex of increased TNF .

TNF refers to both the soluble and transmembrane forms of this molecule. TNF is produced by many cells including macrophages, fibroblasts, T cells, mast cells, and smooth muscle cells. Once it is released in a homotrimeric form it is cleaved by TNF alpha-converting enzymes, and it can then interact with either TNF receptor (TNFR) -1 or -2. This leads to signaling through nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kB) and activation of inflammatory genes

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Veronica Thompson

Journal Manager
Journal of Cytokine Biology