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Distinct functional programming of human fetal and adult monocytes
Elisabeth R Krow-Lucal1, Charles C Kim, Trevor D Burt
1Division of Experimental Medicine, Department of Medicine and.
Insights
Fetal monocytes exhibit distinct responses to cytokines compared to adult monocytes, potentially impacting preterm labor development. This research highlights key immune cell differences in preterm birth pathogenesis.
Area of Science:
- Immunology
- Neonatal Research
- Cellular Biology
Background:
- Preterm birth is a leading cause of infant mortality and neurologic handicap.
- Cytokines like interferon-gamma (IFN-γ) and interleukin-6 (IL-6) are linked to preterm labor, but fetal immune cell responses are poorly understood.
Purpose of the Study:
- To investigate functional differences between fetal and adult human monocytes in response to immune signaling cytokines.
- To explore the implications of these differences in the context of preterm birth.
Main Methods:
- Comparative analysis of basal transcriptional profiles in fetal and adult CD14(+)CD16(-) classical monocytes.
- Assessment of signal transducers and activators of transcription (STATs) phosphorylation in response to cytokines (IFN-γ, IL-6, IL-4).
- Quantification of SOCS3 to IL-6 receptor ratios and evaluation of IFN-γ-induced antigen presentation machinery.
Main Results:
- Fetal monocytes show distinct basal transcriptional profiles and enhanced STAT phosphorylation compared to adult monocytes.
- Fetal monocytes exhibit stronger responses to IFN-γ, IL-6, and IL-4.
- Differences in SOCS3/IL-6 receptor ratios and IFN-γ signaling pathways were observed between fetal and adult monocytes.
Conclusions:
- Primary human fetal and adult monocytes are functionally distinct immune cells.
- These cellular differences may explain differential responses to cytokines involved in fetal development, infection, and preterm labor.
- Understanding these distinctions is crucial for addressing preterm birth and its complications.
Abstract:
Preterm birth affects 1 out of 9 infants in the United States and is the leading cause of long-term neurologic handicap and infant mortality, accounting for 35% of all infant deaths in 2008. Although cytokines including interferon-γ (IFN-γ), interleukin-10 (IL-10), IL-6, and IL-1 are produced in response to in utero infection and are strongly associated with preterm labor, little is known about how human fetal immune cells respond to these cytokines. We demonstrate that fetal and adult CD14(+)CD16(-) classical monocytes are distinct in terms of basal transcriptional profiles and in phosphorylation of signal transducers and activators of transcription (STATs) in response to cytokines. Fetal monocytes phosphorylate canonical and noncanonical STATs and respond more strongly to IFN-γ, IL-6, and IL-4 than adult monocytes. We demonstrate a higher ratio of SOCS3 to IL-6 receptor in adult monocytes than in fetal monocytes, potentially explaining differences in STAT phosphorylation. Additionally, IFN-γ signaling results in upregulation of antigen presentation and costimulatory machinery in adult, but not fetal, monocytes. These findings represent the first evidence that primary human fetal and adult monocytes are functionally distinct, potentially explaining how these cells respond differentially to cytokines implicated in development, in utero infections, and the pathogenesis of preterm labor.
