Effects of cytokines and endotoxin on the intracellular growth of bacteria

Patients with unresolving acute respiratory distress syndrome (ARDS) have p ersistently elevated levels of proinflammatory cytokines in the lungs and c irculation and increased rates of bacterial infections, Phagocytic cells hy peractivated with lipopolysaccharide (LPS), which induces high levels of pr oinflammatory cytokines in monocytic cells, are inefficient in killing inge sted bacteria despite having intact phagocytic activity. On the other hand, phagocytic cells that are activated with an analogue of LPS that does not induce the expression of proinflammatory cytokines effectively ingest and k ill bacteria. We hypothesized that in the presence of high concentrations o f proinflammatory cytokines, bacteria may adapt and utilize cytokines to th eir growth advantage. To test our hypothesis, we primed a human monocytic c ell line (U937) with escalating concentrations of the proinflammatory cytok ines tumor necrosis factor alpha, interleukin-1 beta (IL-1 beta), and IL-6 and with LPS. These cells were then exposed to fresh isolates of three comm on nosocomial pathogens: Staphylococcus aureus, Pseudomonas aeruginosa, and an Acinetobacter sp, In human monocytes primed with lower concentrations o f proinflammatory cytokines (10 to 250 pg) or LPS (1 and 10 ng), intracellu lar bacterial growth decreased. However, when human monocytes were primed w ith higher concentrations of proinflammatory cytokines (1 to 10 ng) or LPS (1 to 10 mu g), intracellular growth of the tested bacteria increased signi ficantly (P < 0.0001). These results were reproduced with peripheral blood monocytes obtained from normal healthy volunteers. The specificity of the c ytokine activity was demonstrated by neutralizing the cytokines with specif ic antibodies. Our findings provide a possible mechanism to explain the fre quent development of bacterial infections in patients with an intense and p rotracted inflammatory response.