Innate Immunity of the Human Newborn Is Polarized Toward a High Ratio of IL-6/TNF-α Production In Vitro and In Vivo

Abstract

Human newborns are susceptible to microbial infection related to incompletely defined aspects of the neonatal immune system. To characterize neonatal innate immunity, we studied production of two early response cytokines in response to Toll-like receptor (TLR)-activating microbial stimuli in vitro: the proinflammatory cytokine tumor necrosis factor (TNF)-␣ and IL-6, a multifunctional cytokine with antiinflammatory and Th2-polarizing properties. Neonatal cord blood responses to multiple TLR agonists, including poly dI:dC (TLR3), lipopolysaccharide (LPS) (TLR4), flagellin (TLR5), and CpG DNA (TLR9), are characterized by a higher IL-6/TNF-␣ ratio than in adult peripheral blood. Robust LPS-induced IL-6 production is due to both neonatal cellular (monocyte-) and humoral (serum-) factors. Remarkably, serum collected from newborns during the first week of life demonstrates higher IL-6/TNF-␣ ratios than does cord blood, associated with elevations of the IL-6-inducible acute phase reactants CRP and LPS-binding protein in the first days of life. A high ratio of stimulus-induced IL-6/TNF-␣ production is likely to profoundly modulate both innate and adaptive immune responses in the human newborn.

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

“…We subsequently investigated the effects of activin-A in LPS-induced responses by neonatal peripheral blood monocytes that express enhanced levels of the LPS receptor, toll-like receptor-4, and respond highly to this stimulus (1,(19)(20)(21). Our findings demonstrated that LPS induced a dramatic increase in the production of IL-1β (P < 0.01), IL-6 (P < 0.01), CXCL8 (P < 0.01), and IL-10 (P < 0.01) by neonatal peripheral blood monocytes, as compared with nonstimulated cells (Figure 5a-d).…”

“…Isolated monocytes were cultured in Roswell Park Memorial Institute medium with GlutaMAX (Invitrogen) supplemented with 2% penicillin/streptomycin (Sigma-Aldrich) at 37 °C, 5% CO 2 for 4, 24, or 48 h in the presence or absence of LPS (1 μg/ ml; Sigma-Aldrich), as previously described (22). We used LPS to examine the effects of activin-A on responses mediated by neonatal monocytes, as these cells express high levels of the LPS receptor, tolllike receptor-4, on their surface and respond highly to this stimulus (1,(19)(20)(21). Moreover, LPS stimulation closely resembles monocyte activation with bacterial stimuli (1).…”

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

“…Erythema toxicum neonatorum, which manifests as rash and fever in term neonates (21,22) is thought to result from a inflammatory response to SE bacteria that penetrate the dermis via hair shafts (23). Furthermore, IL6 levels significantly increase during the first weeks of life in noninfected term neonates, possibly reflecting immune recognition of initial colonization with commensal bacteria such as SE (24). Although all neonates are ubiquitously colonized with SE within days after birth (18), erythema toxicum neonatorum is exceptionally rare in preterm infants (21), suggesting significant GA-related differences in innate immune responses in vivo.…”

Hyper innate responses in neonates lead to increased morbidity and mortality after infection

“…Whether and how the innate immune response in neonates contributes to their susceptibility to infection or TLR stimulation is still controversial. In human, it has been reported that mononuclear cells from cord blood secrete lower amounts of TNF than those from healthy adults in response to TLR agonists (10)(11)(12)(13), whereas other studies draw opposite conclusions (14)(15)(16). Results from studies in mice also conflict because neonates produce either lower (17,18) or higher (19) levels of TNF compared with adults.…”