The relationship between fluctuating cytokine concentrations in plasma and the outcome of sepsis is complex. We postulated that early measurement of the activation of nuclear factor B (NF-B), a transcriptional regulatory protein involved in proinflammatory cytokine expression, may help to predict the outcome of sepsis. We determined NF-B activation in peripheral blood mononuclear cells of 34 patients with severe sepsis (23 survivors and 11 nonsurvivors) and serial concentrations of inflammatory cytokines (interleukin-6, interleukin-1, and tumor necrosis factor) and various endogenous antagonists in plasma. NF-B activity was significantly higher in nonsurvivors and correlated strongly with the severity of illness (APACHE II score), although neither was related to the cytokine levels. Apart from NF-B activity, the interleukin-1 receptor antagonist was the only cytokine tested whose level in plasma was of value in predicting mortality by logistic regression analysis. These results underscore the prognostic value of early measurement of NF-B activity in patients with severe sepsis.Many reports have focused on aspects of the proinflammatory cytokine network, which is believed to be central to the pathophysiology of the sepsis syndrome (5,8). However, the cytokine responses in patients with sepsis appears to vary so much between individuals (10) that the prognostic usefulness of circulating cytokine concentrations is often less than that of clinical variables, such as the acute physiology and chronic health evaluation (APACHE) II or III (9). Other studies indicate that the problem in overwhelming sepsis is not that inflammatory cytokines are expressed but, rather, that their expression is not properly modulated by anti-inflammatory mediators (16,17). Recent investigations by others (3) and ourselves (1) searching for new clinically reliable markers in patients with sepsis have shown that circulating leptin levels, whose secretion is closely linked to the activation of the cytokine cascade (1), may help to predict mortality in sepsis and septic shock.Among several transcriptional regulatory factors involved in immunoregulatory genes expression, nuclear factor kappa B (NF-B) acts at a critical step for directing the transcription of many proinflammatory genes in animal models of inflammatory diseases (6, 7). Investigations regarding the role of NF-B in human inflammatory diseases are scarce (2, 15). So far, no study has aimed to examine in patients with sepsis the relationship between the concentrations of some components of the proinflammatory and anti-inflammatory cytokine response in plasma, NF-B expression in peripheral blood mononuclear cells, and clinical outcome. We hypothesized that severe, fatal sepsis could be distinguished from less severe sepsis by demonstrating greater NF-B activation and decreased anti-inflammatory response. Thus, this study compared the prognostic value of combining measurements of NF-B activity in circulating blood cells and the cytokine profile in plasma in patients with severe sepsis. ...

Leptin production is increased in rodents by administration of endotoxin or cytokines. To investigate whether circulating leptin is related to cytokine release and survival in human sepsis, plasma concentrations of leptin, interleukin (IL)-6, IL-1beta, tumor necrosis factor (TNF)-alpha, soluble TNF receptor type I, IL-1 receptor antagonist (IL-1ra), and the inflammatory modulator IL-10 were measured as soon as severe sepsis (n=28) or septic shock (n=14) developed and every 6 h for 24 h. Patients with sepsis or septic shock had leptin concentrations 2.3- and 4.2-fold greater, respectively, than the control group. There was an independent association for leptin with IL-1ra and IL-10 in both patient groups. By discriminant analysis, leptin and IL-6 were independent predictors of death. These findings suggest that increases in leptin levels may be a host defense mechanism during sepsis.

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