Biological Activity of TNF

The two forms of tumor necrosis factor have similar biological functions in humans, but their cellular sources differ. TNF-a is secreted by macrophages and targets tumor and inflammatory cells. As for its activity, it has cytotoxic effects and induces cytokine secretion. It is also associated with severe weight loss (cachexia) in chronic inflammatory responses. TNF-b, unlike TNF-a, is secreted by certain T cells, particularly T helpers and T cytotoxic cells. It also targets tumor cells where it induces cytotoxic effects and others that are similar to the ones produced by TNF-a. TNF-b can also target macrophages and neutrophils and enhance their phagocytic activity.

One way of investigating the effects of tumor necrosis factor is by looking at the details of the local inflammatory response. Near the site of tissue damage is debris and pathogens which activate a Th cell in the area. This T helper cell secretes interferon-g and TNF-b which, in turn, activate macrophages. The activated macrophages release interleukin-1, interleukin-6, and TNF-a. These cytokines act locally on fibroblasts and endothelial cells to induce coagulation and increase vascular permeability. TNF-a also stimulates expression of an endothelial leukocyte adhesion molecule, ELAM-1, which selectively binds neutrophils. This helps bring neutrophils to the damaged area where they can phagocytize damaged or infected cells.

Usually an acute-phase response accompanies the local inflammatory response. This is a systemic response which involves the induction of fever caused by TNF-a and other cytokines acting on the hypothalamus in the brain. An increased production of certain liver proteins is also associated with this increase in the level of TNF-a and other cytokines. TNF-a can also lead to further T and B-cell activation.

TNF-b also has some interesting biological activity. The interaction of cytotoxic lympocytes, CTLs, encountering a target cell gives a more in depth understanding of this activity. CTLs are activated when their T cell receptors bind to an antigen-MHC Class I complex on the target cell. This complex is stabilized by the CTL's CD8 protein. Granuoles in the cytoplasm of the CTL, which contain TNF-beta, perforin (a pore-forming protein), other toxic cytokines, and esterases, then reorient themselves near the point of contact with the target cell. The release of these substances from the granuoles via exocytosis destroys the target cell, typically in about 15 minutes to 3 hours.

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