Increased plasma levels of CK-18 as potential cell death biomarker in patients with HELLP syndrome

K John,K Schulze-Osthoff,R Hass,S Wielgosz,H Bantel

doi:10.1038/cddis.2013.408

Abstract

HELLP (hemolysis, elevated liver enzymes, low platelets) syndrome represents a life-threatening pregnancy disorder with high fetal and maternal mortality, but its underlying molecular mechanisms remain unknown. Although apoptosis has been implicated in HELLP syndrome, its pathogenic role remains largely unclear. In the present study, we investigated whether the detection of apoptosis by novel plasma biomarkers is of diagnostic value in HELLP patients. For this purpose, we analyzed two biomarkers that specifically detect apoptosis or overall cell death of epithelial cells, such as hepatocytes or placental trophoblasts, through the release of caspase-cleaved or total (caspase-cleaved and uncleaved) cytokeratin-18 (CK-18) in plasma of HELLP patients compared with pregnant as well as non-pregnant healthy women. In addition, caspase activation and cell death were determined in placental tissues of HELLP patients and individuals with normal pregnancy. In contrast to pregnant or non-pregnant healthy controls, we observed significantly increased levels of both caspase-cleaved and total CK-18 in plasma of HELLP patients. Following delivery, CK-18 levels rapidly decreased in HELLP patients. Caspase activation and cell death were also elevated in placental tissues from HELLP patients compared with healthy pregnant women. These data demonstrate not only that apoptosis is increased in HELLP syndrome, but also that caspase-cleaved or total CK-18 are promising plasma biomarkers to identify patients with HELLP syndrome. Thus, further studies are warranted to evaluate the utility of these biomarkers for monitoring disease activity in HELLP syndrome.

Highlights

Apoptosis is triggered by two major signaling routes, namely the extrinsic death receptor and the intrinsic mitochondrial pathway.[15,16,17] Binding of death ligands, such as tumor necrosis factor-a, tumor necrosis factor-related apoptosis-inducing ligand or CD95L, to their respective death receptors leads to death-inducing signaling complex formation, which results in receptor oligomerization and activation of initiator caspase-8 and -10
During apoptosis of epithelial cells, for example, hepatocytes or trophoblasts, caspases cleave the intermediate filament protein CK-18 into fragments that are released in the bloodstream
We found significantly (Po0.01) higher plasma levels of CK-18 fragments in HELLP patients compared with women with normal pregnancy (504.0±93.5 U/l versus 203.9±15.4 U/l; Figure 1a)

Summary

Introduction

Apoptosis is triggered by two major signaling routes, namely the extrinsic death receptor and the intrinsic mitochondrial pathway.[15,16,17] Binding of death ligands, such as tumor necrosis factor-a, tumor necrosis factor-related apoptosis-inducing ligand or CD95L, to their respective death receptors leads to death-inducing signaling complex formation, which results in receptor oligomerization and activation of initiator caspase-8 and -10. The intrinsic pathway is triggered by cellular stress, which initiates the release of mitochondrial proapoptotic mediators followed by activation of initiator caspase-9 and downstream effector caspases. We investigated different cell death biomarkers including caspase-cleaved CK-18 and total (caspase-cleaved and uncleaved) CK-18 in plasma samples from patients with HELLP syndrome compared with individuals with normal pregnancy. We found significantly higher plasma levels of caspase-cleaved and total CK-18 in HELLP syndrome compared with pregnant or non-pregnant healthy controls. Our results suggest that cell death biomarkers might help to early identify patients with increased risk of developing life-threatening HELLP syndrome

Methods

Results

Conclusion