TNF, IL-1, and IL-6 produced during the innate immune response to infection or tissue damage have systemic effects that contribute to host defense and are responsible for many of the clinical signs of infection and inflammatory disease (Fig. 4-14).
• TNF, IL-1, and IL-6 all act on the hypothalamus to induce an increase in body temperature (fever), and these cytokines are therefore called endogenous pyrogens (i.e., host-derived fever-causing agents, to distinguish them from LPS, which was considered an exogenous [microbe-derived] pyrogen). This distinction is mainly of historical significance because we now know that even LPS induces fever by the production of the cytokines TNF and IL-1. TNF and IL-1 are pyrogenic at much lower concentrations than IL-6. Fever production in response to TNF, IL-1, and IL-6 is mediated by increased synthesis of prostaglandins by cytokine-stimulated hypothalamic cells. Prostaglandin synthesis inhibitors, such as aspirin, reduce fever by blocking this action of the cytokines. The advantages of fever are not well understood but may relate to enhanced metabolic functions of immune cells, impaired metabolic functions of microbes, and changes in the behavior of the febrile host that reduce risk of worsening infections and injury.
• IL-1, TNF, and IL-6 induce hepatocytes to express acute-phase reactants, including CRP, SAP, and fibrin-ogen, which are secreted into the blood. Elevated levels of acute-phase reactants are commonly used clinically as signs of infection or other inflammatory processes. The pentraxins CRP and SAP play protective roles in infections, as we discussed earlier in the chapter, and fibrinogen, the precursor of fibrin, contributes to homeostasis and tissue repair.
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