Intracerebroventricular but not intravenous interleukin-1β induces widespread vascular-mediated leukocyte infiltration and immune signal mRNA expression followed by brain-wide glial activation

M. G. Proescholdt, S. Chakravarty, J. A. Foster, S. B. Foti, E. M. Briley, M. Herkenham

Research output: Contribution to journalShort surveypeer-review

87 Scopus citations

Abstract

Interleukin-1β (IL-1β) is a pro-inflammatory cytokine that appears in brain and cerebrospinal fluid following peripheral immune challenges and central infections or injury. We examined the consequences of i.c.v. infusion of IL-1β on mRNA expression of several immune markers and on recruitment of peripheral leukocytes. Awake rats were infused with IL-1β (100 ng/rat) into the lateral ventricle, and 0.5, 2, 4, 8, 12, or 24 h later, animals were killed and their fresh-frozen brains processed for in situ hybridization and immunohistochemistry. Widespread vascular expression of inhibitory factor κBα (IκBα, marker of nuclear factor κBα transcriptional activity) and inducible cyclooxygenase (COX-2) mRNAs at 0.5-2 h was credited to movement of IL-1β along ventricular, subarachnoid, and perivascular pathways to target endothelia that express type 1 IL-1 receptor mRNA. Induction of monocyte chemoattractant protein-1 mRNA and intercellular adhesion molecule-1 (ICAM-1) immunostaining on endothelia began at 0.5-2 h. Leukocytes (neutrophils and monocytes, recognized by morphology and CD45 and ED1 immunostaining) appeared in meninges and blood vessels at 2-4 h and diffusely penetrated the parenchyma at 8-24 h. The leukocytes strongly expressed IL-1β and inducible nitric oxide synthase mRNAs. Beginning at 4-12 h, astrocytes (glial acidic fibrillary protein mRNA and protein and c-fos mRNA) and microglia (ionized calcium-binding adaptor molecule 1 mRNA and protein) showed widespread activation. Other rats received i.v. IL-1β (6 μg/kg). Their brains showed induction of IκBα and COX-2 mRNAs in the vasculature at 2 h but none of the other sequelae. In summary, our data indicate that IL-1β in the cerebrospinal fluid reaches its target receptors on the endothelia via perivascular volume transmission, up-regulates ICAM-1, and triggers a targeted leukocyte emigration and widespread glial activation stimulated perhaps by pro-inflammatory molecules expressed by leukocytes. The dramatic difference between i.c.v. and i.v. routes of administration underscores the potency of IL-1β within the brain to dynamically affect the cellular trafficking component of 'immune privilege'.

Original languageEnglish (US)
Pages (from-to)731-749
Number of pages19
JournalNeuroscience
Volume112
Issue number3
DOIs
StatePublished - Jul 5 2002
Externally publishedYes

Keywords

  • Astrocytosis
  • Cerebrospinal fluid
  • Cyclooxygenase-2
  • Intercellular adhesion molecule-1
  • Meningitis
  • Monocyte chemoattractant protein-1
  • Nuclear factor κB

ASJC Scopus subject areas

  • Neuroscience(all)

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