Rationale behind the use of biologics to inhibit cytokines in various inflammatory diseases
• TNF-α is initially expressed as a transmembrane molecule primarily on the surface of monocytes and macrophages. The extracellular portion is cleaved by TNF-α-converting enzyme to form a soluble molecule that circulates as a homotrimer. TNF-α (and TNF-β from T cells) binds to two receptors, TNF-RI (p55) and TNF-RII (p75), both of which are found on the surface of most cells. Binding of TNF-α to its receptor triggers a variety of intracellular signaling events, inducing production of prostaglandins and proinflammatory cytokines/chemokines, endothelial cell expression of adhesion molecules that help recruit neutrophils and monocytes into the synovium, and synoviocyte/chondrocyte production of matrix metalloproteinases (e.g., collagenase) and upregulation of RANKL with osteoclast activation which can destroy cartilage and bone.
• IL-1 is a proinflammatory cytokine that exists in two forms, IL-1α and IL-1β, which are transcribed from closely related but distinct genes. IL-1α is in the cytosol and is membrane-bound. IL-1β is secreted into the extracellular space after cleavage of pro-IL-1β by IL-1β-converting enzyme (caspase 1). Thus, IL-1β is the predominant form that binds to the IL-1 receptor triggering intracellular signaling leading to a proinflammatory response, (which is synergistic to that induced by TNF-α), B-cell activation and rheumatoid factor production, cartilage degradation by induction of synoviocyte/chondrocyte production of enzymes resulting in proteoglycan loss, and stimulation of osteoclasts causing bone resorption. Notably, cells producing IL-1 also produce IL-1Ra. However, in patients with inflammatory synovitis such as RA, the amount of IL-1Ra in the synovium is produced in insufficient amounts to neutralize the amount of locally produced IL-1.
• IL-5 is produced by Th2 cells and mast cells. It binds to its receptor, IL-5R, and stimulates B-cell growth, immunoglobulin production, and eosinophil activation and survival.
• IL-6 is critical for inflammatory and immune responses. It binds to its receptor, IL-6R, which is constitutively associated with glycoprotein 130 (gp130) on the cell membranes of hepatocytes and some leukocytes. Notably, binding of IL-6 to this cell membrane-bound IL-6R on hepatocytes and leukocytes has an antiapoptotic/antiinflammatory effect. Additionally, there is a soluble form of IL-6R which can bind IL-6, and this complex can interact with gp130 on a wide variety of cells that are usually not affected by IL-6. This soluble IL-6/IL-6R complex is proinflammatory. IL-6 stimulates the development of T helper 17 (Th17) cells which produce IL-17, have a role in the activation of B cells and osteoclasts, help recruit neutrophils, and act synergistically with other cytokines to cause pannus formation.
• IL-17 has six subtypes (A–F) of which IL-17A and IL-17F are most important in inflammation. IL-17 is produced by multiple cells with IL-17A produced mainly by Th17 cells. Th17 cells are derived from CD4+ T cells that have been stimulated with IL-6 or IL-1β and transforming growth factor β. IL-17 dimers bind to the IL-17 receptor on multiple cells resulting in IL-6, IL-8, and granulocyte-macrophage colony-stimulating factor production by epithelial cells, endothelial cells, and fibroblasts, TNF-α production by monocytes, matrix metalloproteinase production, and osteoclastogenesis.
• IL-23 is produced mainly by macrophages and dendritic cells (DCs). It binds to its receptor on multiple cells resulting in enhanced survival of Th17 cells, induction of memory T cells, and stimulation of antigen presentation by DCs.