Inflammasome and caspase-1 inhibition caused by Bcl-2 and Bcl-XL may influence cytokine responses of lipopolysaccharide-stimulated peripheral blood mononuclear cells from septic patients

Abstract

In recent issues of Critical Care, Wu and colleagues [1] and Giamarellos-Bourboulis and colleagues [2] observed that cyt okine responses in diff erent concentrations of lipo polysaccharide (LPS) (1 and 10 pg/μL, respectively) stimulated peripheral blood mononuclear cells (PBMCs) of septic patients and healthy controls. Wu and colleagues found that int erleukin-1beta (IL-1β) production of PBMCs from patients with sepsis was signifi cantly higher than that from controls, whereas Giamarellos-Bourboulis and colleagues found the opposite result. In light of previous research, we would like to off er some remarks. LPS can lead to the activation of nuclear factor-kappaB (NF-κB) and the subsequent generation of pro-IL-1β [3], which is readily processe d into IL-1β by infl ammasome-activated caspase-1 [4]. NF-κB also induces Bcell lymphoma 2 (Bcl-2) and B-cell lymphoma-extra large (Bcl-X L ), both of which could suppress the activation of caspase-1 by inhibiting NLRP1 (pyrin-containing nonobese diabetic-like recep tor 1) and thus suppress the cleavage of pro-IL-1β [5]. When PBMCs were stimulated with low concentrations of LPS, the expression of pro-IL1β could be predominant and functions of infl ammasomes and caspase-1 were still reserved and thus IL-1β production was increased. When PBMCs were stimulated with high concentrations of LPS, the expression of BclX L /Bcl-2 could great ly increase and lead to signifi cant inhibition of caspase-1 and thus the production of IL-1β was decreased, although the expression of pro-IL-1β may not have been infl uenced signifi cantly [2]. Th at may be the reason why the results of the two sets of authors were confl icting. Since Bcl-2/Bcl-X L could be diff erently produced according to various concentrations of LPS, inhibiting Bcl-2/Bcl-X L with reagents like ABT-737 in order to make sure that infl ammasome and caspase-1 are not suppressed in vitro would be necessary when trying to use LPS stimulation to assess the status of PBMCs from patients with sepsis.