Proinflammatory orientation of the interleukin 1 system and downstream induction of matrix metalloproteinase 9 in the pathophysiology of human perinatal white matter damage

J Neuropathol Exp Neurol. 2010 Nov;69(11):1116-29. doi: 10.1097/NEN.0b013e3181f971e4.


A preclinical model showed a direct role of the interleukin 1 (IL-1) system in the pathogenesis of perinatal brain damage, but evidence linking these findings to human white matter damage (WMD) requires confirmation in human cases. We analyzed the IL-1β system using immunohistochemistry to characterize the expression of IL-1 receptors (IL-1R1 and IL-1R2), IL-1R antagonist (IL-1Ra), and induction of downstream effectors in 9 human brains with WMD. Interleukin 1β overexpression was associated with IL-1R1 and IL-1R2 immunoreactivity in areas with WMD; immunolabeling for both was detected on astrocytes and microglia/macrophages. There was no immunoreactivity for these receptors in nondamaged white matter in the same brains. Interleukin-1Ra expression was significantly less upregulated than that of IL-1β. This IL-1β/IL-1Ra imbalance was particularly pronounced in the brains of very preterm versus near-term infants. We additionally found overexpression of matrix metalloproteinase 9 (MMP-9) in WMD areas. The MMP-9 colocalized with IL-1β in microglia/macrophages in affected cerebral areas. These data indicate that there is activation and proinflammatory orientation of the IL-1 system with downstream induction of MMP-9 in perinatal WMD. Because both of these mediators are known to be involved in neural cell injury, we infer that IL-1 pathway activation has a deleterious role in the pathophysiology of WMD in human neonates.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antigens, CD / metabolism
  • Antigens, Differentiation, Myelomonocytic / metabolism
  • Apoptosis / physiology
  • Brain Injuries* / enzymology
  • Brain Injuries* / pathology
  • Brain Injuries* / physiopathology
  • Female
  • Gene Expression Regulation, Enzymologic / physiology
  • Glial Fibrillary Acidic Protein / metabolism
  • Humans
  • Infant
  • Infant, Newborn
  • Interleukin 1 Receptor Antagonist Protein / metabolism
  • Interleukin-1 / metabolism*
  • Male
  • Matrix Metalloproteinase 9 / metabolism*
  • Nerve Fibers, Myelinated / pathology*
  • Signal Transduction / physiology*


  • Antigens, CD
  • Antigens, Differentiation, Myelomonocytic
  • CD68 antigen, human
  • Glial Fibrillary Acidic Protein
  • Interleukin 1 Receptor Antagonist Protein
  • Interleukin-1
  • Matrix Metalloproteinase 9