Evidence of the involvement of caspase-1 under physiologic and pathologic cellular stress during human pregnancy: a link between the inflammasome and parturition

Abstract

Objective: Caspase-1 is a component of the NALP3 inflammasome, a cytosolic multiprotein complex that mediates the processing of pro-inflammatory caspases and cytokines. The inflammasome represents the first line of defense against cellular stress and is a crucial component of innate immunity. Caspase-1 is the enzyme responsible for the cleavage and activation of interleukin (IL)-1 beta, which is a potent pro-inflammatory cytokine, and plays a central role in the mechanisms leading to labor (preterm and term) particularly in the context of intrauterine infection/inflammation. In addition, caspase-1 cleaves IL-18 and IL-33. The objectives of this study were to determine whether there is a relationship between amniotic fluid concentrations of caspase-1 and gestational age, parturition (term and preterm), and intra-amniotic infection/inflammation (IAI).

Study design: A cross-sectional study was conducted including 143 pregnant women in the following groups: (1) mid-trimester of pregnancy (n = 18); (2) term not in labor (n = 25); (3) term in labor (n = 28); (4) preterm labor (PTL) who delivered at term (n = 23); (5) PTL without IAI who delivered preterm (n = 32); (6) PTL with IAI who delivered preterm neonates (n = 17). Caspase-1 concentrations in amniotic fluid were determined by a specific and sensitive immunoassay. Non-parametric statistics were used for analysis.

Results: (1) Caspase-1 was detected in amniotic fluid of women at term, but in none of the mid-trimester samples. (2) Patients in labor at term had a significantly higher median amniotic fluid concentration of caspase-1 than women at term not in labor (term in labor: 10.5 pg/mL, range 0.0-666.0 vs. term not in labor: 5.99 pg/mL, range 0.0-237.4; p < 0.05). (3) Among patients with spontaneous PTL, those with IAI (median 41.4 pg/mL, range 0.0-515.0) had a significantly higher median amniotic fluid caspase-1 concentration than those without IAI who delivered preterm (median 0.0 pg/mL, range 0.0-78.4) and than those who delivered at term (median 0.0 pg/mL, range 0.0-199.5); p < 0.001 for both comparisons.

Conclusions: (1) The presence and concentration of caspase-1 in the amniotic fluid varies as a function of gestational age. (2) Women with spontaneous labor at term had a higher median caspase-1 amniotic fluid concentration than women at term without labor. This suggests that the inflammasome may be activated in spontaneous parturition at term. Since most women with labor do not have intra-amniotic infection, we propose that cellular stress during labor accounts for activation of the inflammasome. (3) Preterm labor associated with infection/inflammation was also associated with a high concentration of caspase-1, suggesting that infection may induce caspase-1 production and activation of the inflammasome. (4) The sequential activation of the inflammasome and caspase-1, leading to interleukin-1 beta processing and secretion, is a candidate pathway leading to the activation of the common pathway of parturition.

Figure 1. Amniotic fluid concentrations of caspases-1 in patients at term

The median amniotic fluid caspases-1 concentration was significantly higher in women in spontaneous labor at term than in those not in labor (term in labor: median 10.5 pg/ml; range (0–666) vs. term not in labor: median 5.99 pg/ml; range (0.00–237.4); p<0.05).

Figure 2. Amniotic fluid concentrations of caspases-1 in women with preterm labor

Among patients with spontaneous PTL, those with intra-amniotic infection and/or inflammation (median 41.4 pg/ml; range: 0.0–515) had a significantly higher median amniotic fluid caspase-1 concentration than those without intra-amniotic infection and/or inflammation who delivered preterm (median 0.0 pg/ml; range: 0.0–78.4) and than those who delivered at term (median 0.0 pg/mL, range 0.0–199.5), p<0.001 for both comparisons.