Activin-A exerts a crucial anti-inflammatory role in neonatal infections.

BACKGROUND: Activin-A is a cytokine with a critical role in infections and associated inflammation in experimental models and humans. Still, the effects of activin-A on neonatal infections remain elusive. Here, we investigated the expression of activin-A in the serum of septicemic preterm and term neonates and in peripheral blood leukocytes stimulated with inflammatory agents in vitro. The role of activin-A in the regulation of inflammatory responses by neonatal leukocytes was delineated. METHODS: Peripheral blood was obtained from 37 septicemic neonates between the first and fifth days postinfection and from 35 healthy controls. Isolated monocytes and lymphocytes were stimulated with lipopolysaccharide (LPS) or phytohemagglutinin (PHA) in vitro in the presence of activin-A. Cell proliferation, cytokine, and chemokine release were investigated. RESULTS: Activin-A was significantly increased in the serum of preterm septicemic neonates. Neonatal leukocytes secreted copious amounts of activin-A following stimulation, pointing to these cells as an essential source of activin-A in the circulation. Of note, treatment of neonatal leukocytes with activin-A during PHA and LPS stimulation resulted in significantly decreased interleukin (IL)-1ß, IL-6, and CXCL8 production, concomitant with a striking increase in the anti-inflammatory mediator, IL-10. CONCLUSION: Our findings uncover activin-A as a novel immunomodulatory agent critical for the control of inflammatory responses in septicemic neonates.

Distinct roles of TLR4 and CD14 in LPS-induced inflammatory responses of neonates.

During infections, pathogens bind to toll-like receptor (TLR)4 and CD14 receptors and induce cytokine release, leading to inflammation. Here, we investigated TLR4 and CD14 expression on peripheral blood leukocytes (PBLs) and their roles in lipopolysaccharide (LPS)-induced cytokine and chemokine release. Full-term and preterm neonates and adults were studied. PBLs were pretreated with anti-TLR4- and anti-CD14-blocking antibodies and stimulated with LPS. Cytokine and chemokine levels were measured in supernatants. TLR4, CD14 expression, and LPS-induced CXCL8 release were higher in neonates, possibly contributing to aberrant inflammation. TLR4 blockade resulted in approximately 3-fold greater suppression of LPS-induced CXCL8 release in preterm neonates (38%) than in adults (14%). CD14 blockade (approximately 80%) in neonates induced approximately 3-fold greater inhibition of CXCL8 release, compared with anti-TLR4 (approximately 30%). Anti-TLR4 partly (50-60%) inhibited IL-10 and TNF-alpha, whereas anti-CD14 completely suppressed their release. Our findings reveal that neonates depend more on TLR4 for CXCL8 release. Furthermore, neonatal LPS-induced CXCL8 release, apart from TLR4/CD14-mediated signaling, is regulated by LPS interactions with other TLRs and/or immune receptors. IL-10 and TNF-alpha release depends on LPS binding not only to CD14/TLR4 but also to CD14 associated with another TLR. Our findings reveal the contribution of TLR4 and CD14 in neonatal cytokine and chemokine release and could aid in design of antagonists to prevent harmful inflammation.

Homozygosity for the double D409H+H255Q allele in type II Gaucher disease.

Homozygosity for D409H has been associated with a unique type III subtype of the disease with a phenotype dominated by severe cardiovascular involvement, whereas neurological findings, if present, are restricted to oculomotor apraxia and features such as visceromegaly are either minimal or absent. Using PCR amplification followed by restriction enzyme analysis, 3 patients (1 Greek, 2 Albanians) were IDentified with the D409H/D409H genotype. All shared a very severe early-onset neurological phenotype that classified them as type II. Amplification and sequencing of the full coding region of the GBA gene revealed that all three patients were homozygous not only for D409H but also for H255Q. Both mutations were present on the same allele, as shown by analysis of the parental DNA. The double D409H+H255Q allele was found in heterozygosity in Greek, Bulgarian and Argentinian patients but was not IDentified in any Spanish patients carrying the D409H mutation.

Inflammatory chemokine expression in the peripheral blood of neonates with perinatal asphyxia and perinatal or nosocomial infections.

AIM: The inflammatory response induced by perinatal infections and asphyxia is considered to participate in neonatal brain damage. Inflammatory responses are characterized by the expression of chemokines. Although chemokine levels have been investigated in healthy newborns, their role during neonatal pathological conditions has not been studied. The aim of our study was to examine chemokine serum levels in asphyxiated and infected neonates. METHODS: Peripheral blood samples were obtained from perinatally asphyxiated and infected neonates during the first days of life and from neonates who developed nosocomial infections. Serum levels of interleukin-8 (IL-8), interferon-gamma-inducible protein-10 (IP-10), monocyte chemoattractant protein-1 (MCP-1), macrophage inflammatory protein-1alpha (MIP-1alpha), and regulated upon activation, normal T cells expressed and secreted (RANTES) were determined. RESULTS: In perinatally asphyxiated neonates, IL-8 levels were significantly elevated on the 1st day of life. In perinatally infected neonates, IL-8 and IP-10 levels were significantly increased on the 1st day of life, while RANTES levels were significantly lower and remained so until the 4th day. In nosocomially infected neonates, IL-8, IP-10 and MIP-1alpha levels were significantly increased on diagnosis of infection. CONCLUSION: The neonatal immune system is able to produce chemokines for the induction of an inflammatory response during perinatal asphyxia and perinatal or nosocomial infections. Blockade of inflammatory chemokines could possibly contribute to the prevention of brain damage.