Ways to Interfere with Lethal Cytokinemia

Abstract

The cytokines tumor necrosis factor alpha (cachectin, TNF) and interleukin-1 beta (IL-1β) are considered crucial mediators of septic shock. Both these cytokines as well as the cytokine interleukin-6 (IL-6) are produced and secreted by mononuclear phagocytes, when these cells encounter bacterial products such as bacterial lipopolysaccharide (endotoxin, LPS), microbial cell wall substances (peptidoglycan, muramyl peptides) and exotoxins (e.g. toxic shock syndrome toxin 1) [1–3]. During various types of septicemia both TNF, IL-1β and IL-6 have been detected in the circulation [4–10]. According to a number of investigators, high concentrations of especially TNF in the circulation appear to indicate a poor prognosis [5, 7, 8]. In a rabbit model, IL-1 and TNF produce a state with the clinical characteristics of septic shock and respiratory distress syndrome [11]. Also in other serious infections, such as cerebral malaria, and in inflammatory states (e.g. the capillary leak syndrome induced by interleukin-2 treatment) the above mentioned cytokines play an important pathophysiological role [12, 13]. The cytokines mentioned probably act in concert with other cytokines like interferon γ and platelet activating factor (PAF) [14, 15]. Under all these circumstances, the patient or the experimental animal may suffer from a state of lethal cytokinemia. Thus, it is logical to investigate whether interference with cytokine production or action is beneficial in severe infection and inflammation. Theoretically, it is possible to interfere with cytokinemia at different levels (Table 1). Each of these interventions will be discussed in more detail in the following paragraphs.