Monocyte Toll-Like Receptor 4 Expression and LPS-Induced Cytokine Production Increase during Gestational Aging

Abstract

Premature newborns are highly susceptible to severe bacterial infections. This is partially due to their immature innate immune system, characterized by decreased neutrophil and monocyte activity as well as by reduced concentrations of complement factors. However, additional mechanisms might be important for innate immunity and are still the subject of considerable debate. The importance of pattern recognition domains such as Toll-like receptors (TLR) has been fully acknowledged within the last few years. Therefore, we investigated age-related monocyte TLR4 expression and lipopolysaccharide-induced cytokine secretion from very low birth weight infants (VLBWI) and from newborns after wk 30 of gestation in comparison to healthy adults. In VLBWI, expression of TLR4 surface protein, detected by flow cytometry, and TLR4-specific mRNA, quantified by real time-PCR, were significantly reduced in comparison to mature infants and to adults. Reduced TLR4 expression was paralleled by significantly diminished ex vivo LPS stimulated IL-1␤, IL-6, and tumor necrosis factor-␣ secretion into whole blood. We conclude that, in VLBWI, the minimized expression of TLR4 contributes to the susceptibility of VLBWI to infections with Gram-negative bacteria due to the lack of cytokines to boost initial immune response. (Pediatr Res 58: 121-124, 2005) Abbreviations CB, cord blood LPS, lipopolysaccharide PAMP, pathogen-associated molecular pattern PB, peripheral blood PBMC, peripheral blood mononuclear cells TLR, Toll-like receptor TNF, tumor necrosis factor VLBWI, very low birth weight infants Bacterial infections are a major cause of neonatal morbidity (1,2), and premature newborns are highly susceptible to infections (3). This increased susceptibility appears to be related to immaturity of the immune system. Maturation of the immune system includes specific humoral and cellular responses as well as nonspecific innate immune mechanisms, such as factors of the complement system and phagocyte activity (3-5).Monocytes and macrophages play a central role in both specific and nonspecific immunity against bacterial, viral, and fungal infection. In VLBWI, a substantial decrease of fully functional phagocytes has recently been reported (6). The Toll protein has been identified as a receptor controlling dorsoventral polarization during embryonic development of Drosophila larvae and serves a defensive function (7). Structures homologous to Toll receptors were found in mammalian cells (8,9) and termed TLR. Within the last few years, 10 human TLR have been described and characterized as important sensors of the innate immune system (9,10). These TLR are phylogenetically conserved and are involved in recognition of microbial PAMP. TLR4 functions as the transmembrane component of the LPS receptor. In addition to LPS, the major glycolipid component of the outer membrane of Gram-negative bacteria, TLR4 recognizes saturated and unsaturated fatty acids such as lipoteichoic acids from Gram-positive bacteria, and heat-shock proteins (8 -10). Binding of these ...

Expression of select immune genes (surfactant proteins A and D, sheep beta defensin 1, and toll-like receptor 4) by respiratory epithelia is developmentally regulated in the preterm neonatal lamb

“…The developmental regulation of surfactant proteins is consistent with previous work on the pathogenesis of respiratory distress syndrome showing antenatal surfactant expression/synthesis in infants and lambs [25,26]. The developmental regulation of TLR4 in whole lung homogenates of lambs is a novel finding that parallels recent work on monocytes of infants showing that developmental regulation of TLR4 expression may contribute to the increased susceptibility to infection by low birth weight infants [27].…”

Responsiveness of human monocytes to the commensal bacterium Staphylococcus epidermidis develops late in gestation

“…TLR4 was expressed on a smaller subset of monocytes in preterm infants, but the expression was also equivalent across groups. Similar levels of mRNA and of protein expressions of TLR2 and TLR4 are reported in neonatal cells of term infants and in adult cells (35), whereas another study found that TLR4 expression increased with increasing GA (36). We conclude that differences in responses to SE in preterm infants are unlikely to result from GA-related increases in TLR2 expression.…”

Attenuated innate immune defenses in very premature neonates during the neonatal period

“…Toll-like receptors (TLRs) play a predominant role as a major family of PRR that act as essential "detectors" in the recognition of microbial pathogens by the innate immune system. We and others have shown that TLR-induced cytokine immune reactivity are profoundly attenuated in cord blood of very preterm neonates and develops asynchronously over the last trimester of gestation (6)(7)(8)(9)(10). These infants also display sustainably high levels of systemic inflammation, indicating a potential immune dysregulation that has also been associated with worsened clinical outcomes (11).…”