IL-4 mediates the delayed neurobehavioral impairments induced by neonatal hepatitis B vaccination that involves the down-regulation of the IL-4 receptor in the hippocampus

Cytokine. 2018 Oct;110:137-149. doi: 10.1016/j.cyto.2018.04.037. Epub 2018 May 9.


We have previously verified that neonatal hepatitis B vaccination induced hippocampal neuroinflammation and behavior impairments in mice. However, the exact mechanism of these effects remain unclear. In this study, we observed that neonatal hepatitis B vaccination induced an anti-inflammatory cytokine response lasting for 4-5 weeks in both the serum and the hippocampus, primarily indicated by elevated IL-4 levels. Three weeks after the vaccination schedule, however, hepatitis B vaccine (HBV)-mice showed delayed hippocampal neuroinflammation. In periphery, IL-4 is the major cytokine induced by this vaccine. Correlation analyses showed a positive relationship in the IL-4 levels between serum and hippocampus in HBV-mice. Thus, we investigated whether neonatal over-exposure to systemic IL-4 influences brain and behavior. We observed that mice injected intraperitoneally with recombinant mouse IL-4 (mIL-4) during early life had similar neuroinflammation and cognition impairment similar to those induced by neonatal hepatitis B vaccination. Next, the mechanism underlying the effects of IL-4 on brain in mice was explored using a series of experiments. In brief, these experiments showed that IL-4 mediates the delayed neurobehavioral impairments induced by neonatal hepatitis B vaccination, which involves the permeability of neonatal blood-brain barrier and the down-regulation of IL-4 receptor. This finding suggests that clinical events concerning neonatal IL-4 over-exposure, including neonatal hepatitis B vaccination and allergic asthma in human infants, may have adverse implications for brain development and cognition.

Keywords: Cytokine; Hepatitis B vaccine; Hippocampus; Interleukin (IL)-4; Neonatal period.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Animals, Newborn
  • Blood-Brain Barrier / drug effects
  • Cytokines / metabolism
  • Down-Regulation / drug effects*
  • Hepatitis B / immunology
  • Hepatitis B Vaccines / adverse effects*
  • Hepatitis B Vaccines / immunology
  • Hepatitis B virus / immunology
  • Hippocampus / drug effects*
  • Hippocampus / metabolism
  • Humans
  • Infant
  • Interleukin-4 / metabolism
  • Mice
  • Mice, Inbred C57BL
  • Nervous System Diseases / chemically induced*
  • Nervous System Diseases / metabolism
  • Receptors, Interleukin-4 / metabolism*
  • Vaccination / adverse effects*


  • Cytokines
  • Hepatitis B Vaccines
  • Receptors, Interleukin-4
  • Interleukin-4