Roles of IFN7 and TNFa in Chronic Inflammation

Two cytokines in particular, IFN-7 and TNF-a, play a central role in the development of chronic inflammation. TH1 cells, NK cells, and TC cells release IFN-7, while activated macrophages secrete TNF-a.

Members of the interferon family of glycoproteins (IFN-a and IFN-p) are released from virus-infected cells and confer antiviral protection on neighboring cells. Exactly which interferon is produced depends on the type of cell infected. IFN-a is produced by leukocytes, IFN-p, often called fibroblast

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Comparison of the structure and function of C/EBP and NF-IL6. (a) Both transcription factors are dimeric proteins containing a leucine-zipper domain (light orange) and a basic DNA-binding domain (blue). (b) C/EBP is expressed constitutively in liver hepatocytes and promotes transcription of albumin and transthyretin genes. During an inflammatory response, binding of IL-1, IL-6, TNF-a, LIF, or OSM to receptors on liver hepatocytes induces production of NF-IL6, which promotes transcription of the genes encoding various acute-phase proteins. Concurrently, C/EBP levels decrease and the levels of albumin and transthyretin consequently decrease.

interferon, is made largely by fibroblasts. IFN-y is produced exclusively by T cells and NK cells. However, IFN-y has a number of pleiotropic activities that distinguish it from IFN-a and IFN-p and contribute to the inflammatory response (Figure 15-15). One of the most striking effects of IFN-y is its ability to activate macrophages. Activated macrophages exhibit increased expression of class II MHC molecules, increased cytokine production, and increased microbicidal activity compared with nonactivated macrophages; thus, they are more effective in antigen presentation and killing of intracellular microbial pathogens. In a chronic inflammatory response, however, the large numbers of activated macrophages release various hydrolytic enzymes and reactive oxygen and nitrogen intermediates, which are responsible for much of the damage to surrounding tissue.

One of the principal cytokines secreted by activated macrophages is TNF-a. The activity of this cytokine was first observed around the turn of the century by the surgeon William Coley. He noted that when cancer patients developed certain bacterial infections, the tumors would become necrotic. In the hope of providing a cure for cancer, Coley began to inject cancer patients with supernatants derived from various bacterial cultures. These culture supernatants, called "Coley's toxins," did induce hemorrhagic necrosis in the tumors but had numerous undesirable side effects, making them unsuitable for cancer therapy. Decades later, the active component of Coley's toxin was shown to be a lipopolysaccharide (endotoxin) component of the bacterial cell wall. This endotoxin does not itself induce tumor necrosis but instead induces macrophages to produce TNF-a. This cytokine has a direct cytotoxic effect on tumor cells but not on normal cells (Figure 15-16a). Potential immunotherapeutic approaches using TNF-a for the treatment of cancer are examined in Chapter 22.

Several lines of evidence indicate that TNF-a also contributes to much of the tissue wasting that characterizes chronic inflammation. For example, mice carrying a TNF-a transgene become severely wasted (Figure 15-16b). In studies by A. Cerami and coworkers, rabbits were found to lose nearly half of their body mass within 2 months of being infected with trypanosomes. These workers subsequently discovered that a macrophage-derived factor was responsible for the profound wasting; they called the factor cachetin. Cloning of the genes for TNF-a and cachetin revealed that they were the same protein.

Activation of macrophages by IFN-a promotes increased transcription of the TNF-a gene and increases the stability of TNF-a mRNA. Both effects result in increased TNF-a production. TNF-a acts synergistically with IFN-y to initiate a chronic inflammatory response. Both cytokines together induce much greater increases in ICAM-1, E-selectin, and class I MHC molecules than either cytokine alone. The increase in intercellular adhesion molecules facilitates the recruitment of large numbers of cells in a chronic inflammatory response.

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Essentials of Human Physiology

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