and also by directly inducing cyclooxygenase-2 as a consequence of signaling through TLR-4, leading to the production of prostaglandin E2. Fever is generally beneficial to host defense; most pathogens grow better at lower temperatures, whereas adaptive immune responses are more intense at elevated temperatures. Host cells are also protected from the deleterious effects of TNF-α at raised temperatures.
The effects of TNF-α, IL-1β, and IL-6 are summarized in Fig. 3.33. One of the most important of these occurs in the liver and is the initiation of a response known as the acute-phase response (Fig. 3.34). The cytokines act on hepatocytes, which respond by changing the profile of proteins that they synthesize and secrete into the blood. In the acute-phase response, blood levels of some proteins go down, whereas levels of others increase markedly. The proteins induced by TNF-α, IL-1β, and IL-6 are called the acute-phase proteins. Several of these are of particular interest because they mimic the action of antibodies, but unlike antibodies they have broad specificity for pathogen-associated molecular patterns and depend only on the presence of cytokines for their production.
One acute-phase protein, the C-reactive protein, is a member of the pentraxin protein family, so called because the proteins are formed from five identical subunits. C-reactive protein is yet another example of a multipronged pathogen-recognition molecule, and it binds to the phosphocholine portion of certain bacterial and fungal cell-wall lipopolysaccharides. Phosphocholine is also found in mammalian cell-membrane phospholipids, but it cannot be bound by C-reactive protein. When C-reactive protein binds to a bacterium, it not only is able to opsonize the bacterium but can also activate the complement cascade by binding to C1q, the first component of the classical pathway of complement activation (see Section 2-7). The interaction with C1q involves the collagen-like parts of C1q rather than the globular heads that make contact with pathogen surfaces, but the same cascade of reactions is initiated.
Mannose-binding lectin (MBL) is another acute-phase protein; it serves as an innate recognition molecule that can activate the lectin pathway of complement (see Section 2-6). MBL is present at low levels in the blood of healthy individuals, but it is produced in increased amounts during the acute-phase response. By recognizing mannose residues on microbial surfaces, MBL can act as an opsonin that is recognized by monocytes, which do not express the macrophage mannose receptor. Two other proteins with opsonizing properties that are also produced in increased amounts during an acute-phase response are the surfactant proteins, SP-A and SP-D. These are produced by the liver and a variety of epithelia. They are, for example, found along with macrophages in the alveolar fluid of the lung, where they are secreted by
Liver Activation of complement Opsonization Bone marrow endothelium Phagocytosis Hypothalamus Decreased viral and bacterial replication Increased antigen processing Increased speciÿc immune response Fat, muscle Dendritic cells Acute-phase proteins (C-reactive protein, mannose-binding lectin) Neutrophil mobilization Increased body temperature Protein and energy mobilization to allow increased body temperature TNF-˜stimulates migration to lymph nodes and maturation Initiation of adaptive immune response IL-1˜/IL-6/TNF-°