Tumor Necrosis Factor-α

TNF-α is a protein of 17 Da produced by sentinel cells in response to TLR stimulation. TNF-α can also be produced by stimulated endothelial cells, T cells, B cells, and fibroblasts. It is produced in both soluble or membrane-bound forms. The membrane-bound form is cleaved from the cell surface by a protease called TNF-α convertase. The soluble TNF-α released in this way triggers the release of chemokines and cytokines from nearby cells and promotes the adherence, migration, attraction, and activation of leukocytes (Figure 3-1). Later, TNF-α facilitates the transition from innate to adaptive immunity by enhancing antigen presentation and T cell activation. TNF-α production is stimulated not only through the toll-like receptors (TLRs) but also by molecules secreted by nerves such as the neurotransmitter neurokinin-1.

TNF-α is an essential mediator of inflammation because in combination with IL-1 it triggers changes in the vascular endothelial cells that line small blood vessels. A local increase in TNF-α causes the classic signs of inflammation, including heat, swelling, pain, and redness. Circulating TNF-α can depress cardiac output, induce microvascular thrombosis, and cause capillary leakage. TNF-α acts on neutrophils (key defensive cells in inflammation; see Chapter 4) to enhance their ability to kill microbes. It attracts neutrophils to sites of tissue damage and increases their adherence to vascular endothelium. It stimulates macrophage phagocytosis and oxidant production. It amplifies and prolongs inflammation by promoting macrophage synthesis of other mediators such as NOX2 and COX-2, and it also activates mast cells. TNF-α induces macrophages to increase its own synthesis together with that of IL-1. As its name implies, TNF-α can kill some tumor cells and virus-infected cells. In high doses, TNF-α may cause septic shock (Chapter 6). There are two TNF receptors: TNFR1 is found on most cells, where it can bind both soluble and cell-associated TNF; and TNFR2 is restricted to the cells of the immune system and responds only to cell-associated TNF.

Based on sequence, functional, and structural similarities, cytokines may be grouped into families. For example, the TNF family consists of multiple proteins, several of which share the ability to kill cells. Other important members include TNF-β (or lymphotoxin) (Chapter 18); CD40L (Chapter 14); FasL (CD95L) (Chapter 18); and TRAIL (Chapter 19).

Interleukin-1

When stimulated through CD14 and TLR4, sentinel cells such as macrophages also produce IL-1α and IL-1β. IL-1β is produced as a large precursor protein that is cleaved by caspase-1 to form the active 17.5-kDa molecule. Ten- to 50-fold more IL-1β is produced than IL-1α, and whereas IL-1β is secreted, IL-1α remains attached to the cell. Therefore, IL-1α only acts on cells in direct contact with the macrophage (Figure 3-2). Transcription of IL-1β messenger RNA (mRNA) occurs within 15 minutes of ligand binding. It reaches a peak 3 to 4 hours later and levels off for several hours before declining. Like TNF-α, IL-1β acts on nearby cells to initiate and amplify inflammation. Thus it acts on vascular endothelial cells to make them adhesive for neutrophils. IL-1 also acts on other macrophages to stimulate their synthesis of NOS2 and COX-2.

During severe infections, IL-1β circulates in the bloodstream where, in association with TNF-α, it is responsible for sickness behavior. Thus it acts on the brain to cause fever, lethargy, malaise, and lack of appetite. It acts on muscle cells to mobilize amino acids, causing pain and fatigue. It acts on liver cells to induce the production of new proteins, called acute-phase proteins, that assist in the defense of the body (Chapter 6).

The most important IL-1 receptors are CD121a and CD121b. CD121a is a signaling receptor, whereas CD121b is not. CD121b thus inhibits IL-1 functions. Soluble CD121b can bind IL-1 and acts as an IL-1 antagonist. IL-1 activity is also regulated by IL-1 receptor antagonist (IL-1RA), an inactive molecule that binds and blocks CD121a. IL-1RA is therefore an important regulator of IL-1 activity and inflammation. It reduces mortality in septic shock and graft-versus-host disease and has antiinflammatory effects (Chapter 6).

IL-1 is a member of a family of cytokines that regulate innate immune responses. Other family members include IL-1RA, IL-18, IL-33, IL-36, IL-37, and possibly IL-38 (Chapter 8 and Appendix 3). All these cytokines signal through a group of closely related receptors. IL-1 and IL-18 are produced as precursor proteins that require activation by inflammatory caspases. Other members of the IL-1 family that play a role in innate immunity include IL-36, which has a proinflammatory effect, and IL-37, which has an antiinflammatory effect.

Interleukin-6

IL-6 is a 22- to 28-kDa glycoprotein produced by macrophages, T cells, and mast cells. Its production is triggered by bacterial endotoxins, IL-1, and TNF-α. IL-6 affects both inflammation and adaptive immunity. It promotes some aspects of inflammation, especially in response to tissue damage and severe infections since it is a major mediator of the acute-phase reaction and of septic shock (Chapter 6). It is an important mediator in antibacterial resistance. It has been suggested that IL-6 regulates the transition from a neutrophil-dominated process early in inflammation to a macrophage-dominated process later. It is also produced by muscles during exercise. IL-6 also has an antiinflammatory role in that it inhibits some activities of TNF-α and IL-1 and promotes the production of IL-1RA as well as a suppressive cytokine called IL-10 (Chapter 20). The IL-6 receptor is a heterodimer consisting of two proteins, gp130 and IL-6R, found on T cells, neutrophils, macrophages, hepatocytes, and neurons.