352 paRI I Immune Effector mechanisms systemic changes observed in the acute inflammatory response. It is composed of five identical polypeptides held response(see Table 15-3). All three cytokines act locally, together by noncovalent interactions. C-reactive protein inducing coagulation and an increase in vascular permeabil- binds to a wide variety of microorganisms and activates com Both TNF-a and IL-1 induce increased expression of plement, resulting in deposition of the opsonin C3b on the adhesion molecules on vascular endothelial cells. For in- surface of microorganisms. Phagocytic cells, which express stance, TNF-a stimulates expression of E-selectin, an endo- C3b receptors, can then readily phagocytose the C3b-coated thelial adhesion molecule that selectively binds adhesion microorganisms molecules on neutrophils IL-1 induces increased expression Many systemic acute-phase effects are due to the com of ICAM-1 and VCAM-1, which bind to integrins on lym- bined action of IL-l, TNF-a and IL-6(see Figure 15-13 phocytes and monocytes. Circulating neutrophils, mono- Each of these cytokines acts on the hypothalamus to induce a cytes, and lymphocytes recognize these adhesion molecules fever response within 12-24 h of the onset of an acute-phase on the walls of blood vessels, adhere, and then move through inflammatory response, increased levels of IL-1, TNF-c and the vessel wall into the tissue spaces. IL-1 and TNF-c also act IL-6(as well as leukemia inhibitory factor(Lif)and onco- on macrophages and endothelial cells to induce production statin M(OSM)) induce production of acute-phase proteins of the chemokines that contribute to the influx of neutro- by hepatocytes TNF-a also acts on vascular endothelial cells phils by increasing their adhesion to vascular endothelial and macrophages to induce secretion of colony-stimulating cells and by acting as potent chemotactic factors. In addition, factors(M-CSF, G-CSF, and GM-Csf). These CSFs stimulate IFN-y and TNF-c activate macrophages and neutrophils, hematopoiesis, resulting in transient increases in the number promoting increased phagocytic activity and increased re- of white blood cells needed to fight the infection lease of lytic enzymes into the tissue spaces The redundancy in the ability of at least five cytokines A local acute inflammatory response can occur without (TNF-a, IL-1, IL-6, LIF, and OSM) to induce production of the overt involvement of the immune system. Often, how- acute-phase proteins by the liver results from the induction ever, cytokines released at the site of inflammation facilitate of a common transcription factor, NF-IL6, after each of these both the adherence of immune-system cells to vascular en- cytokines interacts with its receptor Amino-acid sequencing dothelial cells and their migration through the vessel wall of cloned NF-IL6 revealed that it has a high degree of into the tissue spaces. The result is an influx of lymphocytes, sequence identity with C/EBP, a liver-specific transcription neutrophils, monocytes, eosinophils, basophils, and mast factor(Figure 15-14a). Both NF-IL6 and C/EBP contain a cells to the site of tissue damage, where these cells participate leucine-zipper domain and a basic DNA-binding domain, in clearance of the antigen and healing of the tissue and both proteins bind to the same nucleotide sequence in The duration and intensity of the local acute inflamma- the promoter or enhancer of the genes encoding various liver tory response must be carefully regulated to control tissue proteins. C/EBP, which stimulates production of albumin damage and facilitate the tissue-repair mechanisms that are and transthyretin, is expressed constitutively by hepatocytes. necessary for healing. TGF-B has been shown to play an im- As an inflammatory response develops and the cytokines portant role in limiting the inflammatory response. It also interact with their respective receptors on liver hepatocytes promotes accumulation and proliferation of fibroblasts and expression of NF-IL6 increases and that of C/eBP decreases the deposition of an extracellular matrix that is required for( Figure 15-14b). The inverse relationship between these two proper tissue repa transcription factors accounts for the observation that serum learly, the processes of leukocyte adhesion are of great im- levels of proteins such as albumin and transthyretin decline ortance in the inflammatory response. A failure of proper while those of acute-phase proteins increase during an in- leukocyte adhesion can result in disease, as exemplified by flammatory response leukocyte-adhesion deficiency(see Clinical Focus on page 358) Chronic Inflammation Develops SYSTEMIC ACUTE-PHASE RESPONSE When Antigen Persists The local inflammatory response is accompanied by a sys- Some microorganisms are able to evade clearance by the temic response known as the acute-phase response(Figure immune system, for example by possessing cell-wall compo- 15-13). This response is marked by the induction of fever, nents that enable them to resist phagocytosis. Such organ increased synthesis of hormones such as ACTH and hydro- isms often induce a chronic inflammatory response, result cortisone, increased production of white blood cells (leuko- ing in significant tissue damage. Chronic inflammation also cytosis), and production of a large number of acute-phase occurs in a number of autoimmune diseases in which self- proteins in the liver. The increase in body temperature antigens continually activate T cells. Finally, chronic inflam- inhibits the growth of a number of pathogens and appears to mation also contributes to the tissue damage and wasting enhance the immune response to the pathogen. associated with many types of cancer C-reactive protein is a prototype acute-phase protein The accumulation and activation of macrophages is the hose serum level increases 1000-fold during an acute-phase hallmark of chronic inflammation. Cytokines released by thesystemic changes observed in the acute inflammatory response (see Table 15-3). All three cytokines act locally, inducing coagulation and an increase in vascular permeabil￾ity. Both TNF- and IL-1 induce increased expression of adhesion molecules on vascular endothelial cells. For in￾stance, TNF- stimulates expression of E-selectin, an endo￾thelial adhesion molecule that selectively binds adhesion molecules on neutrophils. IL-1 induces increased expression of ICAM-1 and VCAM-1, which bind to integrins on lym￾phocytes and monocytes. Circulating neutrophils, mono￾cytes, and lymphocytes recognize these adhesion molecules on the walls of blood vessels, adhere, and then move through the vessel wall into the tissue spaces. IL-1 and TNF- also act on macrophages and endothelial cells to induce production of the chemokines that contribute to the influx of neutro￾phils by increasing their adhesion to vascular endothelial cells and by acting as potent chemotactic factors. In addition, IFN- and TNF- activate macrophages and neutrophils, promoting increased phagocytic activity and increased re￾lease of lytic enzymes into the tissue spaces. A local acute inflammatory response can occur without the overt involvement of the immune system. Often, how￾ever, cytokines released at the site of inflammation facilitate both the adherence of immune-system cells to vascular en￾dothelial cells and their migration through the vessel wall into the tissue spaces. The result is an influx of lymphocytes, neutrophils, monocytes, eosinophils, basophils, and mast cells to the site of tissue damage, where these cells participate in clearance of the antigen and healing of the tissue. The duration and intensity of the local acute inflamma￾tory response must be carefully regulated to control tissue damage and facilitate the tissue-repair mechanisms that are necessary for healing. TGF- has been shown to play an im￾portant role in limiting the inflammatory response. It also promotes accumulation and proliferation of fibroblasts and the deposition of an extracellular matrix that is required for proper tissue repair. Clearly, the processes of leukocyte adhesion are of great im￾portance in the inflammatory response. A failure of proper leukocyte adhesion can result in disease, as exemplified by leukocyte-adhesion deficiency (see Clinical Focus on page 358). SYSTEMIC ACUTE-PHASE RESPONSE The local inflammatory response is accompanied by a sys￾temic response known as the acute-phase response (Figure 15-13). This response is marked by the induction of fever, increased synthesis of hormones such as ACTH and hydro￾cortisone, increased production of white blood cells (leuko￾cytosis), and production of a large number of acute-phase proteins in the liver. The increase in body temperature inhibits the growth of a number of pathogens and appears to enhance the immune response to the pathogen. C-reactive protein is a prototype acute-phase protein whose serum level increases 1000-fold during an acute-phase response. It is composed of five identical polypeptides held together by noncovalent interactions. C-reactive protein binds to a wide variety of microorganisms and activates com￾plement, resulting in deposition of the opsonin C3b on the surface of microorganisms. Phagocytic cells, which express C3b receptors, can then readily phagocytose the C3b-coated microorganisms. Many systemic acute-phase effects are due to the com￾bined action of IL-1, TNF- and IL-6 (see Figure 15-13). Each of these cytokines acts on the hypothalamus to induce a fever response. Within 12–24 h of the onset of an acute-phase inflammatory response, increased levels of IL-1, TNF- and IL-6 (as well as leukemia inhibitory factor (LIF) and onco￾statin M (OSM)) induce production of acute-phase proteins by hepatocytes. TNF- also acts on vascular endothelial cells and macrophages to induce secretion of colony-stimulating factors (M-CSF, G-CSF, and GM-CSF). These CSFs stimulate hematopoiesis, resulting in transient increases in the number of white blood cells needed to fight the infection. The redundancy in the ability of at least five cytokines (TNF-, IL-1, IL-6, LIF, and OSM) to induce production of acute-phase proteins by the liver results from the induction of a common transcription factor, NF-IL6, after each of these cytokines interacts with its receptor. Amino-acid sequencing of cloned NF-IL6 revealed that it has a high degree of sequence identity with C/EBP, a liver-specific transcription factor (Figure 15-14a). Both NF-IL6 and C/EBP contain a leucine-zipper domain and a basic DNA-binding domain, and both proteins bind to the same nucleotide sequence in the promoter or enhancer of the genes encoding various liver proteins. C/EBP, which stimulates production of albumin and transthyretin, is expressed constitutively by hepatocytes. As an inflammatory response develops and the cytokines interact with their respective receptors on liver hepatocytes, expression of NF-IL6 increases and that of C/EBP decreases (Figure 15-14b). The inverse relationship between these two transcription factors accounts for the observation that serum levels of proteins such as albumin and transthyretin decline while those of acute-phase proteins increase during an in￾flammatory response. Chronic Inflammation Develops When Antigen Persists Some microorganisms are able to evade clearance by the immune system, for example by possessing cell-wall compo￾nents that enable them to resist phagocytosis. Such organ￾isms often induce a chronic inflammatory response, result￾ing in significant tissue damage. Chronic inflammation also occurs in a number of autoimmune diseases in which self￾antigens continually activate T cells. Finally, chronic inflam￾mation also contributes to the tissue damage and wasting associated with many types of cancer. The accumulation and activation of macrophages is the hallmark of chronic inflammation. Cytokines released by the 352 PART III Immune Effector Mechanisms