of neutrophil-rich blood fractions or by stimulating their production with specific growth factors largely corrects this susceptibility.
3-20 TNF-α is an important cytokine that triggers local containment of infection but induces shock when released systemically.
TNF-α acting on endothelial cells stimulates the expression of adhesion molecules and aids the extravasation of cells such as monocytes and neutrophils. Another important action of TNF-αis to stimulate endothelial cells to express proteins that trigger blood clotting in the local small vessels, occluding them and cutting off blood flow. This can be important in preventing the pathogen from entering the bloodstream and spreading through the blood to organs all over the body. The importance of TNF-α in the containment of local infection is illustrated by experiments in which rabbits were infected locally with a bacterium. Normally, the infection would be contained at the site of the inoculation; if, however, an injection of anti-TNF-α antibody was also given to block the action of TNF-α, the infection spread via the blood to other organs. In parallel, the fluid that has leaked into the tissue in the early phases of an infection carries the pathogen, usually enclosed in dendritic cells, via the lymph to the regional lymph nodes, where an adaptive immune response can be initiated.
Once an infection has spread to the bloodstream, however, the same mechanisms by which TNF-α so effectively contains local infection instead becomes catastrophic (Fig. 3.32). Although produced as a membrane-associated cytokine, TNF-α can be cleaved by a specific protease, TACE (TNF-α-converting enzyme, which is encoded by the ADAM17 gene), and released from the membrane as a soluble cytokine. The presence of infection in the bloodstream, or sepsis, is accompanied by a massive release of soluble TNF-α from macrophages in the liver, spleen, and other sites throughout the body. The systemic release of TNF-α into the bloodstream causes vasodilation, which leads to a loss of blood pressure and increased vascular permeability; this in turn leads to a loss of plasma volume and eventually to shock, known in this case as septic shock because the underlying cause is a bacterial infection. The TNF-α released in septic shock also triggers blood clotting in small vessels throughout the body—known as disseminated intravascular coagulation—which leads to the massive consumption of clotting proteins, so that the patient’s blood cannot clot appropriately. Disseminated intravascular coagulation frequently leads to the failure of vital organs such as the kidneys, liver, heart, and lungs, which are quickly compromised by the failure of normal blood perfusion; consequently, septic shock has a very high mortality rate.
Mice with defective or no TNF-α receptors are resistant to septic shock but are also unable to control local infection. Mice in which the ADAM17 gene has been selectively inactivated in myeloid cells are also resistant to septic shock, confirming that the release of soluble TNF-αinto the circulation both depends on TACE and is the main factor responsible for septic shock. Blockade of TNF-α activity, either with specific antibodies or with soluble proteins that mimic the receptor, is a successful treatment for several inflammatory disorders, including rheumatoid arthritis. However, these treatments have been found to reactivate tuberculosis in some apparently well patients with evidence of previous infection (as demonstrated by skin test), which is a direct demonstration of the importance of TNF-α in keeping infection local and in check.
3-21 Cytokines made by macrophages and dendritic cells induce a systemic reaction known as the acute-phase response.
As well as their important local effects, the cytokines produced by macrophages and dendritic cells have long-range effects that contribute to host defense. One of these is the elevation of body temperature, which is caused
Local infection with Systemic infection with Gram-negative bacteria Gram-negative bacteria (sepsis)