Tumor Necrosis Factor Alpha

The cytokine that has been implicated as the most direct result of endotoxin administration and of the systematic proinflammatory response is TNF— a. Along with IL-1 and IL-6, TNF is believed to be the major endogenous mediator of LPS. TNF was discovered in the mid-1970s by a group lead by Old, but was not isolated and purified until the mid-1980s. Its purification allowed the cloning of its encoding gene and subsequently allowed its production in sufficient quantities to allow extensive study(9). Initially, two seemingly different compounds were isolated, Cachectin isolated due to its role in wasting disease and TNF due to its antitumor activity(61). Later both were shown to be one and the same molecule(62). TNF—a is a 17 kilodalton polypeptide proposed to be a primary mediator associated with gramnegative (LPS induced) bacterial sepsis and endotoxiemia as well as a number of beneficial host effects including that associated with its namesake (9,63,64). Although some casual relationships have been described that appear to underscore the importance of TNF as at least one of several key mediators in endotoxemia and septicemia, attempts to attenuate the deleterious host response to TNF - a have been notably unsuccessful. Michie et al. (38) list four primary findings supporting the importance of TNF in endotoxemia and sepsis:

First, tumor necrosis factor has been detected in the circulation of laboratory animals after the administration of a lethal injection of endotoxin. Second, infusion of tumor necrosis factor in laboratory animals caused physiological changes similar to those observed in animals with gram-negative septicemia. Third, C3H HeJ mice, which are unable to elaborate tumor necrosis factor because of a genetic defect, are resistant to otherwise lethal doses of endotoxin. Finally, passive immunization of endotoxin-sensi-tive mice with antiserum to tumor necrosis factor substantially reduced the lethal effects of endotoxin and pretreatment of baboons with a monoclonal antibody to tumor necrosis factor prevented their deaths after injection with a lethal dose (LDioo) of live E. coli organisms.

Because the half life associated with a given molecule of TNF is very short (a few minutes), and it may disappear before symptoms are observed, studies designed to correlate the levels of TNF with the degree of severity of sepsis have been variable (60). Attempts to attenuate the effects of septicemia by preventing TNF production would have to be undertaken before it can become apparent that such an effort would even be needed (i.e., when a patient is asymptomatic). Studies have also shown similar sepsis-associated increases in IL-1 and IL-6. While the septic studies implicate TNF in a systemic role, other studies have also implicated TNFs role in specific organ responses such as ARDS, inflammatory bowel disease, Crohn's disease, and rheumatoid arthritis. Modern monoclonal antibodies have been successful in attenuating the TNF role in the latter two diseasesh.

Although TNF can induce systemic inflammatory response similar to endo-toxemia and septic shock, it is the state of the host rather than the dose ("seed versus soil") that is believed by many to determine the final outcome of endotoxin exposure (60). Suffice it to say that TNF is an important letter of a cytokine network, which forms the language of inflammatory response, the exact combination and sequence and amounts of which have not been deciphered in spelling out the fatal septic epithet.

Even with overwhelming evidence of a major TNF role in the endotoxin inflammatory response, the exact interplay of the various cytokines has been called into question by other findings. Brouckaert and Fiers (60) provide several points that suggest a more moderate role of TNF in the host response to LPS:

1. TNF levels do not discriminate between survivors and nonsurvivors

2. patients treated with TNF have higher levels of TNF than septic shock patients but the toxicity does not mimic septic shock and is reversible

3. Offner et al. (53) (1990) suggest that sustained low doses of TNF are correlated with fatal septic shock outcome (such as those potentially present in parenteral nutrition and other chronic states of medical intervention)

4. in bacterial peritonitis TNF proves to be protective rather than detrimental

5. hampering anticytokine strategies is the observation that low levels of some cytokines may be necessary for protection from excessive inflammatory responses hREMICADETM (infliximab) for the treatment of Crohn's disease and rheumatoid arthritis (anti-TNFa chimeric monoclonal antibody) launched in 2002 by Centocor in the U.S.

The types of (endotoxin) "bad seeds" are described in Chapter 3 and none-ndotoxin modulators in Chapter 5. The "seeds" refer to either the specific endo-toxic conformation of LPS, the presence of additional microbes and/or microbial by-products, or a combination of both. Types of "bad soil" may include a number of contributing host states such as blood factors (e.g., lipid content, complement, LPS receptor availability, etc.), additional disease states, and even genetic predispositions of the host. Westendorp et al. (66) studied the inheritability of cytokine production ("the proportion of the population variation attributable to genetic variation") using statistical methods involving 190 first-degree relatives of 61 patients of meningococcal disease as well as 26 monozygotic twins. Cytokine production was stimulated and measured in whole-blood by an ex vivo method. According to the authors, families with low TNF production had a 10 times greater risk of fatal outcome, while a 20 times increased risk of fatality was (retrospectively) associated with high IL-10 production. Families with both low TNF and high IL-10 production had the greatest risk. Therefore, pro-inflammatory TNF was seen to act as a protector against fatal meningococcal disease progression while the anti-inflammatory IL-10 cytokine was viewed as a hindrance to the body's efforts against the bacterial infection. The authors state, "taken together the data suggest that innate capacity to produce cytokines contributes to familial susceptibility for fatal meningococcal disease." However, the authors also indicate that it is premature to generalize these findings with regard to other types of infections.

In another study implying that the susceptibility to endotoxic shock may reside to some degree in a patient's genome, a multicenter study found that specific sequences of the TNF-a gene (TNF2 as opposed to the TNF1 allele) were statistically associated with a higher number of cases of septic shock and death (3.7 fold increased risk) due to septic shock (67). The later two findings can now be understood in terms of TLR polymorphisms, which are heritable differences in the ultimate endotoxin signaling receptors to be discussed in some detail in Chapter 4 and in regard to sepsis in Chapter 17. The "right" types and amounts of both pro-inflammatory and anti-inflammatory cytokines desired for survival are far from clear, though the body knows and is very sensitive to changes instigated by outsiders including both man-made concoctions and infecting invaders. Quakyi et al. (68) maintain that because endotoxin-associated preparations are generally heterogeneous, associated non-LPS cellular components may provide crosscurrents in the cytokine mix resulting in beneficial effects that could possibly modulate some of the toxic effects of TNF.

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