TNF/3 lymphotoxin

Tumour necrosis factor (TNF) was originally described as a factor produced following exposure of Bacille-Calmette-Guerin-treated animals to bacterial endotoxin. It was so named because it possessed the ability to necrotise tumours. This factor is now named TNF-a to distinguish it from another, related cytokine lymphotoxin, which is sometimes referred to as TNF-/J Alternative names for TNF-a include cachectin and cytotoxin. Its primary cellular source in the body is the activated macrophage, but some other cell types (e.g. NK cells, astrocytes, some lymphocytes, fibroblasts, many tumour cells, endothelial cells and neutrophils) have also been shown to synthesise this cytokine. 

IL-6 expression can be activated in neutrophils upon exposure to GM-CSF and TNF, whilst IL-3, G-CSF, y-interferon and lymphotoxin do not induce expression of this cytokine. Expression of IL-6 has been identified by analysis of mRNA levels and by protein analysis. Following GM-CSF exposure, expression is detectable by 2 h, maximal by 6 h and then returns to base-line levels. LPS, PMA (but not fMet-Leu-Phe) and cycloheximide also induce IL-6 transcripts. The finding that this protein-synthesis inhibitor increases mRNA levels suggests either that transcription is regulated by a short-lived repressor, or else that decay of its mRNA may be regulated by a short-lived RNase. 

NK cells express receptors for numerous monokines constitutively, and produce IFN-y and other NK-derived cytokines rapidly in response to stimulation by monokines [18, 19]. Freshly isolated CD56 "s human NK cells are the primary source of NK cell-derived immuno-regulatory cytokines, including IFN-y, TNF-(3 (lymphotoxin), IL-10, IL-13 and GM-CSF, whereas the CDSb NK-cell subset produces consistently negligible amounts of these cytokines following stimulation with recombinant monokines in vitro [20]. The production of cytokines by NK cell subsets was investigated following activation with phorbol esters (e.g. phorbol 12-myristate 13-acetate (PMA)) and ionomycin. 

Fig. 14.3 Tumor necrosis factor (TNF) locus with some of the polymorphic sites known within the TNF locus. C2, C4, complement C2, C4 Ch, chromosome HLA, human leukocyte antigen HSP, heat shock protein LTA, lymphotoxin A LTB, lymphotoxin B MHC, major histocompatibility complex. (Reproduced from ref 74 by permission of Future Medicine Ltd.)...

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 . 

Etanercept is a recombinant fusion protein consisting of two soluble TNF p75 receptor moieties linked to the Fc portion of human IgG (Figure 36-4) it binds TNF- molecules and also inhibits lymphotoxin-a. 

As with the anti-TNFa mAbs, neither an immunoadhesin containing type 1 TNF receptor sequences (TNF-RI-Fc fusion protein) (79) nor type II receptor sequences (TNF-RII-Fc fusion protein, etanercept) reduced mortality in patients with septic shock (80). Flowever, unlike the case of the mAh therapy, there appeared to be a significant, dose-dependent increase in mortality with the TNF-RII-Fc construct (doses tested were 0.15 mg/kg, 0.45 mg/kg and 1.5 mg/kg as a single infusion). The reasons for this result and the discrepancy with the mAh data are not clear. It may be related to the lymphotoxin-binding capacity of the TNF-R fusion protein, to the capacity of some mAbs to lyse membrane-associated TNFa-expressing monoytes, or to chance observation. 

Mechanism of action Etanercept [ee TAN er sept] is a genetically engineered fusion protein composed of two identical chains of the recombinant human TNF-receptor p75 monomer fused with the Fc domain of human IgGi. This soluble fusion protein binds two molecules of TNF, and prevents them from binding to cellular receptors. The protein does not discriminate between TNF-a and TNF- 3 (lymphotoxin). [Note Because TNF is important in modulating cellular immune responses to infection and tumors, there is some concern about the long-term use of etanercept.]... 

IL-2 appears to cause a generalized increase in capillary permeability, reduced systemic vascular resistance, fluid shifts and low effective circulating blood volume. It is not known if the vascular effects are a direct effect of IL-2 or due to IL-2 induced release of other mediators such as IFN, IL-1, TNF, and lymphotoxin [11, 20]. 

Lymphotoxin Tumor necrosis factor- (TNF-/ ) T cells Target cells kills... 

Tumour necrosis factor (TNF) receptor family. The mediators themselves include TNF (a P) and lymphotoxin a, and there are at least four receptor subtypes. 

Tumor necrosis factors (TNF) are lymphokines that exist in either an a or P form they are capable of causing in vivo hemorrhagic necrosis of certain tumor cells, but not affecting normal cells. They also have been used as experimental anticancer agents but can also induce shock when bacterial endotoxins cause their release. TNFa contains 157 amino acids and is produced by macrophages, eosinophils, and NK cells. TNpp is a lymphotoxin and contains 171 amino acids. ... 

---