Interleukin‐1, Tumour Necrosis Factor and Treatment of the Septic Shock Syndrome

Abstract

Treating the septic shock syndrome with antibodies that block only endotoxin has its limitations. Other targets for treating septic shock include neutralizing antibodies to the complement fragment C5a, platelet activating factor antagonists and blockade of endothelial cell leukocyte adhesion molecules. Specific blockade of the pro-inflammatory cytokines interleukin-1 (IL-1) or tumour necrosis factor (TNF) reduces the morbidity and mortality associated with septic shock. Moreover, blocking IL-1 and TNF likely has uses in treating diseases other than septic shock. Use of neutralizing antibodies to TNF or IL-1 receptors has reduced the consequences of infection and inflammation, including lethal outcomes in animal models. The IL-1 receptor antagonist, a naturally occurring cytokine, blocks shock and death due to Escherichia coli as well as ameliorates a variety of inflammatory diseases. Soluble TNF and IL-1 surface receptors, which bind their respective cytokines. also ameliorate disease processes. Clinical trials are presently evaluating the safety and efficacy of anticytokine therapies either alone or in combination.

Serum corticosterone, interleukin‐1 and tumour necrosis factor in rat experimental endotoxaemia: comparison between Lewis and Wistar strains

“…These data confirm in two strains of rat the sequential release of TNF and IL-1 activity accompanied by increased CCS following LPS in vivo described in other species (Dinarello, 1991). The CCS response appears to be more sensitive to LPS than is cytokine release, as seen with responses to 0.01 mg kg-' (Figure 3): this may be a genuine phenomenon, since for example, the CCS increase occurs at lower doses of LPS than does pyresis (Derijk et al, 1991) rather than a lack of sensitivity of our cytokine assays.…”

“…Amongst the many activities of IL-1 and TNFa, their roles as mediators of septic shock are well established, and cytokine levels are transiently elevated in animal models of shock and gram-negative sepsis (Dinarello, 1991). Lipopolysaccharide (LPS) is frequently used to induce release of IL-1 and TNFx, and this is associated with an increase in circulating corticosteroids.…”

Increased distribution and expression of CD64 on blood polymorphonuclear cells from patients with the systemic inflammatory response syndrome (SIRS)

“…In response to invasion by microbial pathogens both cytokines are generated by components of the immune system and blood levels of G‐CSF are increased during the leucocytosis accompanying bacterial infections [33]. High concentrations of the pro‐inflammatory cytokines IL‐1 and TNF α are associated with tissue damage and multiple organ failure [34,35], but there is no uniform agreement as to whether circulating levels of these cytokines and others, including G‐CSF, are consistently elevated in patients with sepsis [36–40]. It seems unlikely that CD64‐bearing PMNs originate from an environment with high local concentrations of IFN γ since it is generally thought that PMNs do not re‐enter the circulation after tissue extravasation, even though lymph from thoracic ducts of patients with SIRS contains a disproportionately high number of PMNs [41].…”

The emerging role of MIF in septic shock and infection

“…Over the years, a number of in vitro and in vivo studies have established that the host response to infection requires a complex interplay of both cellular and humoral mediators [1][2][3][4]. The earliest event in this response has been shown to be the recognition by the host, in a non-antigen specific manner, of various microbial cell surface components.…”