Tnf

Skeletal muscle

Insulin resistance

FIGURE 4-14 Local and systemic actions of cytokines in inflammation. TNF, IL-1, and IL-6 have multiple local and systemic inflammatory effects. TNF and IL-1 act on leukocytes and endothelium to induce acute inflammation, and both cytokines induce the expression of IL-6 from leukocytes and other cell types. TNF, IL-1, and IL-6 mediate protective systemic effects of inflammation, including induction of fever, acute-phase protein synthesis by the liver, and increased production of leukocytes by the bone marrow. Systemic TNF can cause the pathologic abnormalities that lead to septic shock, including decreased cardiac function, thrombosis, capillary leak, and metabolic abnormalities due to insulin resistance.

In severe infections, TNF may be produced in large amounts and causes systemic clinical and pathologic abnormalities. If the stimulus for cytokine production is sufficiently strong, the quantity of TNF may be so large that it enters the blood stream and acts at distant sites as an endocrine hormone (see Fig. 4-14). The principal systemic actions of TNF are the following:

• TNF inhibits myocardial contractility and vascular smooth muscle tone, resulting in a marked fall in blood pressure, or shock.

• TNF causes intravascular thrombosis, mainly as a result of loss of the normal anticoagulant properties of the endothelium. TNF stimulates endothelial cell expression of tissue factor, a potent activator of coagulation, and inhibits expression of thrombomodulin, an inhibitor of coagulation. The endothelial alterations are exacerbated by activation of neutrophils, leading to vascular plugging by these cells. The ability of this cytokine to cause necrosis of tumors, which is the basis of its name, is mainly a result of thrombosis of tumor blood vessels.

• Prolonged production of TNF causes wasting of muscle and fat cells, called cachexia. This wasting results from TNF-induced appetite suppression and reduced synthesis of lipoprotein lipase, an enzyme needed to release fatty acids from circulating lipoproteins so that they can be used by the tissues.

A complication of severe bacterial sepsis is a syndrome called septic shock, which may be caused by LPS released from gram-negative bacteria (in which case it is called endotoxin shock) or lipoteichoic acid from grampositive bacteria. Septic shock is characterized by vascular collapse, disseminated intravascular coagulation, and metabolic disturbances. This syndrome is due to LPS- or lipoteichoic acid-induced TLR signaling leading to the production of TNF and other cytokines, including IL-12, IFN-y, and IL-1. The concentration of serum TNF may be predictive of the outcome of severe bacterial infections. Septic shock can be reproduced in experimental animals by administration of LPS, lipoteichoic acid, or TNF. Antagonists of TNF can prevent mortality in the experimental models, but clinical trials with anti-TNF antibodies or with soluble TNF receptors have not shown benefit in patients with sepsis. The cause of this therapeutic failure is not known, but it may be because other cyto-kines elicit the same responses as TNF, an example of redundancy.

Acute inflammation may cause tissue injury because the effector mechanisms that phagocytes use to kill microbes are also highly toxic to host tissues. The proteolytic enzymes and reactive oxygen species produced by phagocytes that accumulate at a site of infection can injure host cells and degrade extracellular matrix if they are generated in large quantities, especially if the microbes resist being killed and continue to stimulate the innate immune responses. In fact, much of the pathology associated with infections is due to the inflammatory responses and not direct toxic effects of the microbes. Acute inflammation also causes tissue damage in the setting of autoimmune diseases, in which case neutro-phils and macrophages accumulate and become activated secondarily to stimulation of the adaptive immune system by self antigens (see Chapter 14). As in inflammation induced by infections, TNF, IL-1, IL-6, and IL-12 are the key inducers of inflammation in autoimmune disease. Antagonists against TNF, IL-1, and IL-12 and antibodies against IL-6 receptors are in clinical use or in trials to reduce inflammation in patients with some of these diseases, such as rheumatoid arthritis, inflammatory bowel disease, and psoriasis.

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