In recent issues of Critical Care, Wu and colleagues  and Giamarellos-Bourboulis and colleagues  observed that cytokine responses in different 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 interleukin-1beta (IL-1β) production of PBMCs from patients with sepsis was significantly higher than that from controls, whereas Giamarellos-Bourboulis and colleagues found the opposite result. In light of previous research, we would like to offer some remarks.
LPS can lead to the activation of nuclear factor-kappa-B (NF-κB) and the subsequent generation of pro-IL-1β , which is readily processe d into IL-1β by inflammasome-activated caspase-1 . NF-κB also induces B-cell lymphoma 2 (Bcl-2) and B-cell lymphoma-extra large (Bcl-XL), both of which could suppress the activation of caspase-1 by inhibiting NLRP1 (pyrin-containing nonobese diabetic-like receptor 1) and thus suppress the cleavage of pro-IL-1β . When PBMCs were stimulated with low concentrations of LPS, the expression of pro-IL-1β could be predominant and functions of inflammasomes 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 Bcl-XL/Bcl-2 could greatly increase and lead to significant inhibition of caspase-1 and thus the production of IL-1β was decreased, although the expression of pro-IL-1β may not have been influenced significantly . That may be the reason why the results of the two sets of authors were conflicting.
Since Bcl-2/Bcl-XL could be differently produced according to various concentrations of LPS, inhibiting Bcl-2/Bcl-XL with reagents like ABT-737 in order to make sure that inflammasome 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.
Bcl-2: B-cell lymphoma 2; Bcl-XL: B-cell lymphoma-extra large; IL-1β: interleukin-1beta; LPS: lipopolysaccharide; NF-κB: nuclear factor-kappa-B; PBMC: peripheral blood mononuclear cell.
The authors declare that they have no competing interests.
Giamarellos-Bourboulis EJ, van de Veerdonk FL, Mouktaroudi M, Raftogiannis M, Antonopoulou A, Joosten LA, Pickkers P, Savva A, Georgitsi M, van der Meer JW, Netea MG: Inhibition of caspase-1 activation in gram-negative sepsis and experimental endotoxemia.
Bruey JM, Bruey-Sedano N, L uciano F, Zhai D, Balpai R, Xu C, Kress CL, Bailly-Maitre B, Li X, Osterman A, Matsuzawa S, Terskikh AV, Faustin B, Reed JC: Bcl-2 and Bcl-XL regulate proinflammatory caspase-1 activation by interaction with NALP1.