Thiopental and Nuclear Factor κB: Some Questions

Abstract

In Reply:—We appreciate the points raised by Drs. Haeberle and Kiefer and offer the following responses.First, Drs. Haeberle and Kiefer state that the concentration of thiopental used in our study would be “much higher than plasma concentrations noted during clinical practice or in other models presenting inhibitory effects of thiopental on IFN-γ production.” However, in addition to the study cited by them, much higher plasma concentrations of thiopental have been reported to occur in patients during long-term administration of thiopental for the treatment of intracranial hypertension—concentrations that are comparable to those used in the present study. 1Moreover, as already pointed out in detail within the article, tissue concentrations of thiopental in organs that play a central role in the development of nosocomial infections may be even 3 to 10 times higher than the plasma concentrations. 2Second, Drs. Haeberle and Kiefer note, “inhibition of NF-κB activation may not reflect general immune suppression.” However, we neither conclude nor state this. In our article, we wrote that our results “may provide a molecular mechanism for some of the immunosuppressing effects associated with thiopental treatment.” Nuclear factor κB (NF-κB) plays a crucial role in the control of the activation, proliferation, and differentiation of neutrophils, macrophages, and T and B lymphocytes. 3Therefore, the reduced function of immune cells “would be consistent with an inhibition of NF-κB by thiopental.”Third, the authors suggest, “it would be helpful to give some more information beyond that provided by the authors in their statement that ‘other transcription factors may be involved.’” In view of the large amount of data included within our article, communicating additional results about the effect of barbiturates on other transcription factors was far beyond the scope of the paper. However, we do have evidence that thiopental may also inhibit the nuclear factor of activated T cells in human T lymphocytes. These findings were presented at the 10th Meeting of the European Society of Anesthesiologists (2002) in Nice, France. 4Fourth, Drs. Haeberle and Kiefer state, “cytokine expression is regulated in a cell-type and stimuli-specific manner.” We fully agree with this statement. To briefly recapitulate, we examined the effects of anesthetics in T lymphocytes on the tumor necrosis factor–dependent activation of NF-κB, as well as the cytokine expression induced by phorbol-12-myristate-13-acetate (125 ng/ml) in mononuclear cells. Therefore, the cited study 5is not comparable because cytokine expression in mononuclear cells was induced by lipopolysaccharide. Likewise, in this study, the effects of thiopental were investigated at concentrations of less than 200 μg/ml, whereas we used 400-μg/ml thiopental. At this lower concentration, Takaono et al. 5did not note a significant effect; however, a trend toward inhibition could be observed.Later in their letter, Haeberle and Kiefer state that “ketamine decreases cytokine production…and suppresses endotoxin-induced NF-κB activation.” These studies used whole blood, 6a human glioma cell line, or extracts of mice brain. 7Kawasaki et al. 6observed the inhibition of tumor necrosis factor–induced interleukin 6 and interleukin 8 production by ketamine at concentrations higher than 100 μg/ml. In contrast, we used 60 μg/ml or less ketamine in our study. Sakai et al. , 7while observing an inhibition of lipopolysaccharide-induced NF-κB activation at 30 μg/ml, used a glioma cell line and brain extracts in these experiments. Therefore, we believe that the comparability of these studies with ours is impaired because of the different experimental settings and the fact that cytokine expression is, indeed, “regulated in a cell-type and stimuli-specific manner.”