Defective Production of IL-18 and IL-12 by Cord Blood Mononuclear Cells Influences the T Helper-1 Interferon Gamma Response to Group B Streptococci

Abstract

Human neonates are uniquely susceptible to group B streptococcal (GBS) infections. We have shown that neonatal mixed mononuclear cells have a deficiency in the production of the T helper-1 (Th-1) cytokine, interferon gamma (IFN-␥), and that incubation of neonatal neutrophils with recombinant IFN-␥ corrects these neutrophil defects. IL-12 and the more recently described IL-18 are also Th-1 type cytokines that are able to induce the production of IFN-␥ in the presence of bacteria and bacterial products. We examine the ability of GBS to induce the production of IFN-␥, IL-18, and IL-12 by cord blood mixed mononuclear cells and compared these results with the IFN-␥, IL-18, and IL-12 response of mixed mononuclear cells from adult blood. We demonstrate that cord blood mixed mononuclear cells produced significantly less IL-18 is a recently described member of the IL-1 cytokine family, which was initially defined as IFN-␥-inducing factor (1). IL-18 gene expression and/or protein secretion has been observed in macrophages (2), dendritic cells (3), mononuclear cells (4), keratinocytes (5), chondrocytes (6), pituitary and adrenal cells (7), astrocytes and microglia (8), and intestinal epithelial cells (9). Studies have elucidated a broad array of effector functions implicating IL-18 as an important regulator of both innate and acquired immune responses (10, 11). In animals, IL-18 contributes to protective immunity against a variety of pathogens, including Cryptococcus, Leishmania, Staphylococcus, Salmonella,.IL-12 is also an integral immune regulator, which promotes Th-1 responses while suppressing Th-2 responses (16,17). IL-12 is primarily produced by macrophages and dendritic cells and has been shown to induce the production of IFN-␥ by T cells and natural killer (NK) cells (18). Recent studies have focused on the interaction between IL-18 and IL-12 in certain inflammatory responses. In Th-1 immune responses, IL-18 and IL-12 are important cytokines that may synergistically stimulate IFN-␥ production and enhance NK and T cell-mediated cytotoxicity (19). Recent studies implicate the interaction of these Th-1 cytokines in the development of autoimmune diseases and suggest that regulating their function may be therapeutically beneficial (20,21).Early-onset GBS infections in neonates often lead to sepsis and severe septic shock, with an approximate 5-15% mortality rate (22)(23)(24)

Preterm Infants Have Deficient Monocyte and Lymphocyte Cytokine Responses to Group B Streptococcus

“…Our adult kinetic studies confirmed that both cytokines were produced in large part by T and B cells (especially after PHA stimulation), and we were able to detect lymphocytic proliferation in response to GBS that was impaired in CBMC. Reduced lymphocyte IFN-␥ may reflect impaired IL-12 and IL-18 production induced by GBS (22) and, together with reduced IL-10, might suggest a bias toward Th2 responses to GBS in the newborn. IL-13 was indeed induced by GBS in our system, but the levels were relatively low and did not vary between newborns and adults.…”

Postnatal Development of Monocyte Cytokine Responses to Bacterial Lipopolysaccharide

“…There have been many reports indicating that the immune system is deficient in capacity to mount Th1 responses at birth (13,14) and later during infancy (21), but there have, in contrast, been only limited studies (4) on how this response capacity develops with age.…”

“…However, what is clear is that the ratio of IL-6 to TNF-␣ is higher in newborn cord blood monocytes compared with adult monocytes (7,12). Similarly, there is general agreement that production of interferon (IFN)-␥ and IL-18 in cord blood is reduced compared with adults (13,14), however, this may not necessarily apply to all cell types (15).…”

Induction of Apoptosis by Herpes Simplex Virus-1 in Neonatal, But Not Adult, Neutrophils

“…It has been reported that pro-inflammatory cytokines such as tumor necrosis factor (TNF)-␣, interferon (INF)-␥, IL-1␤, IL-2, granulocyte-macrophage colony-stimulating factor (GM-CSF), and IL-15 can delay neutrophil apoptosis (24). However, some of theses cytokines, INF-␥, IL-12, and IL-18 (25) have been reported to have lower expression levels in neonatal neutrophils. This could explain why neonatal neutrophils are more susceptible to undergo apoptosis after HSV infection than adult neutrophils.…”