Abstract
Background: Cleaving ligands and receptors of the tumor necrosis factor (TNF) superfamily can critically regulate the induction of apoptosis. Matrix metalloproteinases (MMPs) such as MMP-9 and tumor necrosis factor-α-converting enzyme (TACE) have been shown to cleave CD95-Ligand (CD95L) and TNF/(TNF receptor-1) TNFR1 which induce phagocytosis induced cell death (PICD) in adult monocytes. This process is reduced in neonatal monocytes. Methods: Here we tested in vitro, whether Escherichia coli infection mounts for activation of MMP-9 and TACE in monocytes and whether this process regulates PICD. Results: The surface expression of TACE was most prominent on infected adult monocytes. In contrast, surface presentation of MMP-9 was highest on infected neonatal monocytes. Selective blocking of MMP-9 decreased CD95L secretion, while inhibition of TACE left CD95L secretion unaltered. Blocking of MMP-9 increased surface CD95L (memCD95L) expression on infected neonatal monocytes to levels comparable to infected adult monocytes. Moreover, MMP-9 inhibition raised PICD of infected neonatal monocytes to levels observed for infected adult monocytes. In contrast, TACE inhibition decreased PICD in infected monocytes. Addition of extracellular TNF effectively induced memCD95L presentation and PICD of adult monocytes and less of neonatal monocytes. Conclusion: MMP-9 activity is crucial for downregulating cell-contact dependent PICD in E. coli infected neonatal monocytes. By this mechanism, MMP-9 could contribute to reducing sustained inflammation in neonates.
Highlights
Perinatal mortality and morbidity is often caused by preterm delivery
We have previously shown that monocytes derived from neonatal cord blood (CBMO) undergo less apoptosis following infection with E. coli or group B-streptococci (GBS), while monocytes from adult donors (PBMO) show a strong apoptotic response to infection [4,5]
Previous work revealed that CBMO show less CD95L-expression, TNFR1-internalization and tumor necrosis factor (TNF) secretion compared to PBMO
Summary
Perinatal mortality and morbidity is often caused by preterm delivery. modern intensive care has increased the number of surviving preterm infants, they may suffer from complications and lifelong handicaps. Previous work revealed that CBMO show less CD95L-expression, TNFR1-internalization and TNF secretion compared to PBMO This difference could be the result of a distinct posttranslational regulation of these pro-apoptotic factors in adults and neonates. To better understand differences in PICD between neonatal and adult monocytes we here study the regulation of MMP-9 and TACE expression in CBMO and PBMO after E. coli infection. By blocking experiments with distinct metalloproteinase inhibitors we investigate the role of MMP-9 and TACE for surface-expression and secretion of death ligands in monocytes from adults and neonates. To check whether expression profiles were correlated to enzyme activities and to exclude the possibility that infection caused alterations in the presence of MMP-9 and TACE only coincidentally, we performed a shedding assay for CD62L as an indicator for TACE-activity (Figure 1C).
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