Biological activities of TNF

The availability of large quantities of recombinant TNF-a facilitates rigorous investigation of the effects of this cytokine on cells in vitro, as well as its systemic in vivo effects. Like most cytokines, TNF-a exhibits pleiotropic effects on various cell types. The major biological responses induced by this cytokine include  

At low concentrations, TNF-a activates a range of leukocytes which mediate selected elements of both specific and non-specific immunity. These TNF-a actions include  

In addition, TNF-a influences immunity indirectly by promoting synthesis and release of a variety of additional cytokines, including interferons, IL-1, IL-6, IL-8 and some CSFs. 

TNF-a also plays a prominent role in mediating the inflammatory response and, indeed, this may be its major normal physiological role. It promotes inflammation by a number of means, including  

therefore, promotes various aspects of immunity and inflammation. Blockage of its activity, e.g. by administration of anti-TNF-a antibodies, has been shown to compromise the body s ability to contain and destroy pathogens. 

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The biologic activity of TNF-ct is mediated by binding of soluble or membrane-bound TNF- trimers to cell-surface TNF- receptors. Infliximab binds to soluble TNF- trimers with high affinity, preventing the cytokine from binding to its receptors. Serum TNF- concentrations may actually increase because binding to infliximab slows TNF-rt clearance. Infliximab also binds to membrane-bound TNF-a and neutralizes its activity. Furthermore, the Fc portion of human IgGl... 

Neutralizes the biological activity of TNF-a by binding with high affinity to the soluble transmembrane form of TNFa and inhibits binding of TNFa with its receptors... 

TNF is inactivated rapidly in and cleared from the circulation. The clearance mechanism seems to consist of two phases. First, after the release of TNF in circulation, inactivation of the biologic activity of TNF is observed. Thereafter, clearance of the TNF protein takes place, mainly by the kidney and to a much lesser extent by the liver (Beutler et al. 1985, Pessina et al. 1987). 

Initial classification of some cytokines was also undertaken on the basis of the specific biological activity by which the cytokine was first discovered (e.g. TNF exhibited cytotoxic effects on some cancer cell lines CSFs promoted the growth in vitro of various leukocytes in clumps or colonies). This, too, proved an unsatisfactory classification mechanism, as it was subsequently shown that most cytokines display a range of biological activities (e.g. the major biological function of TNF is believed to be as a regulator of both the immune and inflammatory response). More recently, primary sequence analysis of cytokines coupled to determination of secondary and tertiary structure reveal that most cytokines can be grouped into one of six families (Table 8.2). 

A third biological activity of IL-2 pertinent to immunostimulation is its ability to promote the growth of NK cells. It also promotes further differentiation of NK cells, forming lymphokine-activated killer (LAK) cells, which exhibit an enhanced ability to kill tumour cells or virally infected cells directly. NK cells express the P and y IL-2 receptor subunits only thus, their stimulation by IL-2 requires elevated concentrations of this cytokine. NK cells are also activated by a variety of additional cytokines, including all interferons and TNF. 

Infliximab neutralizes the biological activity of tumor necrosis factor alpha (TNF ) by high-affinity binding to its soluble and transmembrane forms and inhibits TNF receptor binding. Infliximab does not neutralize TNF (lymphotoxin ), a related cytokine that uses the same receptors as TNF . 

A variety of medical conditions are now believed to be caused or exacerbated by overproduction of certain cytokines in the body. A variety of pro-inflammatory cytokines, including IL-6 and IL-8 as well as TNF, have been implicated in the pathogenesis of both septic shock and rheumatoid arthritis. Inhibiting the biological activity of such cytokines may provide effective therapies for such conditions. This may be achieved by administration of monoclonal antibodies raised against the target cytokine, or administration of soluble forms of its receptor which will compete with cell surface receptors for cytokine binding. 

TNF-a, IL-12, and GMCSF (CaudeU et aL, 2002). However, when IL-24 is over expressed via an adenovirus gene delivery system, it selectively induces apoptosis of cancer cells but not normal cells (Madireddi et at, 2000 Mhashilkar et at, 2001). The mechanisms that distinguish the different biological activities of lL-24 are currently under intense investigation. Finally, lL-26 was identified as a molecule secreted by T-cells infected with herpesvirus saimiri (Knappe et at, 2000). lL-26 has been shown to be up-regulated in NK and T cells by 1L-2/1L-12 and anti-CD3 antibody. However, the specific functional properties of lL-26 have not been reported. 

Most of the IL-1 activity in plasma is from IL-lp, IL-la existing mainly in an intracellular or membrane-associated IL-1 shares many of its functions with TNF, but important differences between IL-1 and TNF exist. For example, IL-1 is in general not toxic, and TNF is a potent cytotoxic effector (see the Biological Actions of TNF section). One of their shared functions is the induction of expression of the vascular cell adhesion molecule (VCAM) by endothelial cells. Studies have indicated that TNF may be more important than IL-1 in induction of VCAM expression at least in the nasal mucosa. ... 

Interleukin-2 Human recombinant lL-2 aldesleukin, proleukin des-alanyl-1, serine-125 human lL-2) differs from native lL-2 in that it is not glycosylated, has no amino terminal Ala, and has an Ser substituted for the Cys at amino acid 125. The potency of the preparation is represented in International Units in a lymphocyte proliferation assay such that 1.1 mg of recombinant lL-2 protein equals 18 million International Units. Aldesleukin has the following in vitro biologic activities of native lL-2 enhancement of lymphocyte proliferation and growth of lL-2-dependent cell lines enhancement of lymphocyte-mediated cytotoxicity and killer cell activity and induction of interferon-7 activity. In vivo administration of aldesleukin in animals produces multiple immunologic effects in a dose-dependent manner. Cellular immunity is profoundly activated with lymphocytosis, eosinophilia, thrombocytopenia, and release of multiple cytokines e.g., TNF-a, lL-1, interferon-7). Aldesleukin is indicated for the treatment of adults with metastatic renal cell carcinoma and melanoma. Administration of aldesleukin has been associated with serious cardiovascular toxicity resulting from capillary leak syndrome, which involves loss of vascular tone and leak of plasma proteins and fluid into the extravascular space. Hypotension, reduced organ perfusion, and death may occur. An increased risk of disseminated infection due to impaired neutrophil function also has been associated with aldesleukin treatment. 

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