354 paRI I Immune Effector mechanisms intermediates, which are responsible for much of the damage to HOOC COOH HOOC COOH surrounding tissue NH2 H2N NH2 One of the principal cytokines secreted by activated macro- phages is TNF-c. The activity of this cytokine was first ob- served 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 can- C/EPB NF-IL6 cer patients with supernatants derived from various bacterial cultures. These culture supernatants, called"Coley's toxins, ∠ Cytokine did induce hemorrhagic necrosis in the tumors but had nu hepatocytes merous undesirable side effects, making them unsuitable for ancer therapy. Decades later, the active component of Coley's LC/EP toxin was shown to be a lipopolysaccharide(endotoxin)com- ponent 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 treat T Tr umin 」 Albumin ment of cancer are examined in Chapter 22 Several lines of evidence indicate that tnf-a also contri- butes to much of the tissue wasting that characterizes chronic T Serum amyloid A inflammation. For example, mice carrying a TNF-a trans- gene become severely wasted(Figure 15-16b). In studies by A Cerami and coworkers, rabbits were found to lose nearly FIGURE 15-14 Comparison of the structure and function of C/EBP half of their body mass within 2 months of being infected and NF-IL6.(a)Both transcription factors are dimeric proteins con- with trypanosomes. These workers subsequently discovered taining a leucine-zipper domain (light orange) and a basic DNA- that a macrophage-derived factor was responsible for the binding domain(blue).(b)C/EBP is expressed constitutively in liver profound wasting: they called the factor cachetin. Cloning of hepatocytes and promotes transcription of albumin and transthyretin the genes for TNF-a and cachetin revealed that they were the genes During an inflammatory response, binding of IL-1, IL-6, TNF-cx, same protein. LIF, or OSM to receptors on liver hepatocytes induces production of Activation of macrophages by IFN-o promotes increased NF-IL6, which promotes transcription of the genes encoding vario encoding various transcription of the TNF-a gene and increases the stability of acute-phase proteins. Concurrently, C/EBP levels decrease and the lev- TNF-a mRNA. Both effects result in increased TNF-a pro- els of albumin and transthyretin consequently decrease duction. TNF-a acts synergistically with IFN-y to initiate a chronic inflammatory response. Both cytokines together in- duce 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 interferon, is made largely by fibroblasts. IFN-y is produced exclusively by T cells and NK cells. However, IFN-y has CHRONIC INFLAMMATORY DISEASES number of pleiotropic activities that distinguish it from IFN-a Recent studies suggest that regions of plump endothelial cells and IFN-B and contribute to the inflammatory response(Fig- resembling HEVs appear along the vasculature in tertiary are 15-15).One of the most striking effects of IFN-y is its abil- extralymphoid sites of chronic infection. These HEV-like re- ity to activate macrophages. Activated macrophages exhibit gions, which appear to be sites of lymphocyte extravasa- increased expression of class ll MHC molecules, increased tion into the inflamed tissue, express several mucins(e. g, Gly kine production, and increased microbicidal activity com- CAM-1, MAdCAM-1, and CD34)that are often displayed ed with nonactivated macrophages; thus, they are more normal HEVs. Several cytokines, notably IFN-y and TNF-a, ffective in antigen presentation and killing of intracellular that are associated with chronic inflammation may play a role microbial pathogens. In a chronic inflammatory response, in the induction of HEV-like regions along the vasculature however, the large numbers of activated macrophages release These HEv-like regions have been observed in a number various hydrolytic enzymes and reactive oxygen and nitrogen of chronic inflammatory diseases in humans, includinginterferon, is made largely by fibroblasts. IFN- is produced exclusively by T cells and NK cells. However, IFN- has a number of pleiotropic activities that distinguish it from IFN- and IFN- and contribute to the inflammatory response (Fig￾ure 15-15). One of the most striking effects of IFN- is its abil￾ity to activate macrophages. Activated macrophages exhibit increased expression of class II MHC molecules, increased cytokine production, and increased microbicidal activity com￾pared 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 macro￾phages is TNF-. The activity of this cytokine was first ob￾served 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 can￾cer patients with supernatants derived from various bacterial cultures. These culture supernatants, called “Coley’s toxins,” did induce hemorrhagic necrosis in the tumors but had nu￾merous 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) com￾ponent of the bacterial cell wall. This endotoxin does not itself induce tumor necrosis but instead induces macrophages to produce TNF-. This cytokine has a direct cytotoxic effect on tumor cells but not on normal cells (Figure 15-16a). Potential immunotherapeutic approaches using TNF- for the treat￾ment of cancer are examined in Chapter 22. Several lines of evidence indicate that TNF- also contri￾butes to much of the tissue wasting that characterizes chronic inflammation. For example, mice carrying a TNF- trans￾gene 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- and cachetin revealed that they were the same protein. Activation of macrophages by IFN- promotes increased transcription of the TNF- gene and increases the stability of TNF- mRNA. Both effects result in increased TNF- pro￾duction. TNF- acts synergistically with IFN- to initiate a chronic inflammatory response. Both cytokines together in￾duce 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. CHRONIC INFLAMMATORY DISEASES Recent studies suggest that regions of plump endothelial cells resembling HEVs appear along the vasculature in tertiary extralymphoid sites of chronic infection. These HEV-like re￾gions, which appear to be sites of lymphocyte extravasa￾tion into the inflamed tissue, express several mucins (e.g., Gly￾CAM-1, MAdCAM-1, and CD34) that are often displayed on normal HEVs. Several cytokines, notably IFN- and TNF-, that are associated with chronic inflammation may play a role in the induction of HEV-like regions along the vasculature. These HEV-like regions have been observed in a number of chronic inflammatory diseases in humans, including 354 PART III Immune Effector Mechanisms (a) HOOC COOH L L L L L L L L L L NH2 HOOC COOH L L L L L L L L H2N H2N L L NH2 DNA DNA C/EPB NF-IL6 (b) ↑C/EPB ↑ Albumin ↓C/EPB ↑NF-IL6 ↑ Transthyretin Cytokine ↓ Albumin ↓ Transthyretin ↑ C-reactive protein ↑ Serum amyloid A ↑ Fibrinogen Liver hepatocytes FIGURE 15-14 Comparison of the structure and function of C/EBP and NF-IL6. (a) Both transcription factors are dimeric proteins con￾taining 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-, 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 lev￾els of albumin and transthyretin consequently decrease.