Cytokine Measurements in Septic Shock

The cytokines interleukin-1 (IL-1) and tumor necrosis factor (TNF) affect nearly every cell type by increasing the production of substances that promote local and systemic inflammatory processes. These include the up-regulation of the genes for cyclooxygenase and nitric oxide synthases, the release of platelet-activating factor, and the synthesis of endothelial adhesion molecules. Vasodilation, reduced tissue oxidation, and leukocyte-mediated necrosis are thought to contribute to organ failure and death in patients with septic shock. Although IL-1 and TNF are capable of inducing shock individually, of greater biological relevance is the synergistic action of these two cytokines.

In animal models of disease, the roles of IL-1 and TNF have been defined by specifically inhibiting each cytokine. The anticytokine strategies for treatment of septic shock follow the same approach. Interleukin-1 can be blocked by reducing its synthesis [1]; infusing IL-1-receptor antagonist [2-4]; or administering soluble (extracellular) IL-1 receptors [5]. Blocking TNF can be accomplished by reducing its synthesis, infusing neutralizing antibodies, or administering TNF-binding proteins that are the soluble forms of p55 or p75 TNF receptors [6, 7]. These agents are now being assessed in clinical trials.

What triggers the synthesis and release of IL-1 and TNF? The most potent agonist is bacterial lipopolysaccharide (or endotoxin), although it is important to remember that exotoxins from gram-positive bacteria and some fungal products can also stimulate IL-1 and TNF synthesis. Human blood monocytes are exquisitely sensitive to endotoxin, producing IL-1 and TNF in vitro in response to 25 to 50 pg/mL of endotoxin, a concentration achieved in the circulation during septic shock as reported by Casey and colleagues [8] …