Neonatal macrophages express elevated levels of interleukin‐27 that oppose immune responses

Abstract

SummaryMicrobial infections are a major cause of infant mortality worldwide because of impaired immune defences in this population. The nature of this work was to further understand the mechanistic limitations of the neonatal and infant immune response. Interleukin-27 (IL-27) is a heterodimeric cytokine of the IL-12 family that is produced primarily by antigenpresenting cells and is immunosuppressive toward a variety of immune cell types. We show that IL-27 gene expression is elevated in cord bloodderived macrophages relative to macrophages originating from healthy adults. We also evaluated the duration over which elevated IL-27 gene expression may impact immune responses in mice. Age-dependent analysis of IL-27 gene expression indicated that levels of IL-27 remained significantly elevated throughout infancy and then declined in adult mice. Flow cytometric analysis of intracellular cytokine-stained splenocytes further confirmed these results. Interleukin-27 may be induced during pregnancy to contribute to the immunosuppressive environment at the fetal-maternal interface because we demonstrate dose-responsive gene expression to progesterone in macrophages. Neutralization of IL-27 in neonatal macrophages improved the ability of these cells to limit bacterial replication. Moreover, neutralization of IL-27 during incubation with the Mycobacterium bovis bacillus Calmette-Gu erin vaccine augmented the level of interferon-c elicited from allogeneic CD4 + T lymphocytes. This suggests that blocking IL-27 during vaccination and infection may improve immune responses in newborn and infant populations. Furthermore, mice will be a suitable model system to further address these possibilities.

Comments on the elevated IL-27 expression in neonates: Relevance between detecting nucleotide sequence or protein synthesized

“…Those plasma levels were promptly assessed, and a statistically significant decrease (p-level < 0.001) of human IL-27 levels was evident for the UCB relative to the HD group (mean ± SEM = 1.2 ng/ml ± 0.4 and 3.0 ng/ml ± 0.6, for UCB and HD, respectively). This finding does not mirror that described by Kraft et al [1]. However, discrepancies could be due to (i) the genetic background of the population studied (USA vs. Brazil), or (ii) the type of sample analyzed (mRNA vs. protein).…”

“…As a result, discrepancies in cytokine levels between adult and neonatal immune cells have been reported, particularly in the IL-27 data. Elevated levels of IL-27 mRNA were detected in the murine model [1]. Similar results were obtained with human cord-blood derived macrophages as well.…”

“…We have read with great interest the recent article by Kraft et al [1] which describes the remarkable recent advances related to the developmental and functional mechanisms of the human neonatal immune system. Several aspects of the comparison between adult and neonate characteristics were described, with substantial attention paid to the rapid maturity of the neonatal immunity.…”

IL-27 inhibits IFN-γ induced autophagy by concomitant induction of JAK/PI3 K/Akt/mTOR cascade and up-regulation of Mcl-1 in Mycobacterium tuberculosis H37Rv infected macrophages

“…IL-27R deficient macrophages during M. tuberculosis infection show increased Th1 response due to enhanced production of IL-12p40, IL-6 and TNF-␣ (Holscher et al, 2005). Addition of IL-12 and at the same time neutralization of IL-27 enhances killing of intracellular MTB by augmenting production of IFN-␥, TNF-␣ and IL-18 (Jung and Robinson, 2014;Robinson and Nau, 2008;Kraft et al, 2013). Above informations clearly suggest that IL-27 plays a critical role in tuberculosis immunity.…”

Ontogeny of early life immunity

“…high production of anti-inflammatory IL-6 and IL-10). Similarly, human and murine neonatal macrophage production of immunosuppressive IL-27, a heterodimeric cytokine of the IL-12 family, peaks during infancy [65]. Both human cord blood- and neonatal murine-derived splenic macrophages express IL-27 genes and proteins at elevated levels compared to adult counterparts.…”