Activation of the maternal immune system induces endocrine changes in the placenta via IL-6
Open accessAbstract
Activation of the maternal immune system in rodent models sets in motion a cascade of molecular pathways that ultimately result in autism- and schizophrenia-related behaviors in offspring. The finding that interleukin-6 (IL-6) is a crucial mediator of these effects led us to examine the mechanism by which this cytokine influences fetal development in vivo. Here we focus on the placenta as the site of direct interaction between mother and fetus and as a principal modulator of fetal development. We find that maternal immune activation (MIA) with a viral mimic, synthetic double-stranded RNA (poly(I:C)), increases IL-6 mRNA as well as maternally-derived IL-6 protein in the placenta. Placentas from MIA mothers exhibit increases in CD69+ decidual macrophages, granulocytes and uterine NK cells, indicating elevated early immune activation. Maternally-derived IL-6 mediates activation of the JAK/STAT3 pathway specifically in the spongiotrophoblast layer of the placenta, which results in expression of acute phase genes. Importantly, this parallels an IL-6-dependent disruption of the growth hormone-insulin-like growth factor (GH-IGF) axis that is characterized by decreased GH, IGFI and IGFBP3 levels. In addition, we observe an IL-6-dependent induction in pro-lactin-like protein-K (PLP-K) expression as well as MIA-related alterations in other placental endocrine factors. Together, these IL-6-mediated effects of MIA on the placenta represent an indirect mechanism by which MIA can alter fetal development.
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Maternal inflammation may play a role, given that maternal stress has been associated with increased inflammatory markers and altered cytokine production during pregnancy.
“Moreover, maternal inflammation may play a role, given that maternal stress has been associated with increased inflammatory markers and altered cytokine production during pregnancy [136–139].”
From Brain structural and functional outcomes in the offspring of women experiencing psychological distress during pregnancy (2024) · cites this paper as [139]
The Discussion reports that experimentally induced maternal immune activation increases IL-6 and other pro-inflammatory cytokines during pregnancy, supporting a role for maternal inflammation. It does not establish the claimed association between maternal stress and increased inflammatory markers or altered cytokine production; the study's immune challenge is not maternal stress. (LLM, conf=0.82)
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Poly I‐C Induces Early Embryo Loss in F344 Rats: a Potential Role for NK Cells
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The maternal interleukin-17a pathway in mice promotes autism-like phenotypes in offspring
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Prenatal maternal immune activation causes epigenetic differences in adolescent mouse brain
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Epigenetic changes at gene promoters in response to immune activation in utero
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Update on the neurodevelopmental theory of depression: is there any 'unconscious code'?
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- Authors
- Hsiao, E. Y., & Patterson, P. H.
- Affiliations
- California Institute of Technology (US)
- Corresponding author
- Hsiao, Elaine Y.
- Venue
- Brain, Behavior, and Immunity
- Publisher
- Elsevier BV
- Published
- 2011-05
- Volume
- 25
- Issue
- 4
- Pages
- 604-615
- ISSN
- 0889-1591 (ISSN-L)
- PMC
- PMC3081363
- OpenAlex
- W2165444002
- Cited by
- 402
- References
- 95
- Citations by year
- 2026: 21 · 2025: 36 · 2024: 28 · 2023: 29 · 2022: 28 · 2021: 30 · 2020: 27 · 2019: 25 · 2018: 26 · 2017: 16 · 2016: 16 · 2015: 25 · 2014: 24 · 2013: 26 · 2012: 29
- FWCI
- 9.65
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Brain Behavior and Immunity (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- CaltechAUTHORS (California Institute of Technology) (submittedVersion)
- Funders
- National Institutes of Health (NIH/NRSA 5 T32 GM07737)
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › Reproductive System and Pregnancy
- Life Sciences › Neuroscience › Biological Psychiatry › Tryptophan and brain disorders
- Health Sciences › Medicine › Epidemiology › Preterm Birth and Chorioamnionitis
- Keywords
- maternal immune activation, interleukin-6, placenta, poly(I:C), JAK/STAT3 signaling, spongiotrophoblast, decidual macrophages, uterine NK cells, growth hormone/insulin-like growth factor axis, IGFBP-3, placental endocrine function, autism spectrum disorder, schizophrenia, fetal development, cytokines
- MeSH terms
- Analysis of Variance, Animals, Behavior, Animal, Decidua, Female, Granulocytes, Killer Cells, Natural, Macrophages, Male, Mice, Inbred C57BL, Placenta, Poly I-C, Pregnancy, Pregnancy Proteins, Prenatal Exposure Delayed Effects, RNA, Double-Stranded, RNA, Messenger, Virus Diseases, Signal Transduction, Interleukin-6, Mice, Knockout, Maternal Exposure, Fetal Development, Mice, Endophenotypes
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Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
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