Intracerebroventricular but not intravenous interleukin-1beta induces widespread vascular-mediated leukocyte infiltration and immune signal mRNA expression followed by brain-wide glial activation.
Interleukin-1beta (IL-1beta) 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-1beta on mRNA expression of several immune markers and on recruitment of peripheral leukocytes. Awake rats were infused with IL-1beta (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 kappa(B)alpha (Ikappa(B)alpha, marker of nuclear factor kappa(B)alpha transcriptional activity) and inducible cyclooxygenase (COX-2) mRNAs at 0.5-2 h was credited to movement of IL-1beta 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-1beta 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-1beta (6 microg/kg). Their brains showed induction of Ikappa(B)alpha and COX-2 mRNAs in the vasculature at 2 h but none of the other sequelae. In summary, our data indicate that IL-1beta 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-1beta within the brain to dynamically affect the cellular trafficking component of 'immune privilege'.
Proescholdt
M G
MG
Section on Functional Neuroanatomy, National Institute of Mental Health, Bethesda, MD 20892-4070, USA.
Chakravarty
S
S
Foster
J A
JA
Foti
S B
SB
Briley
E M
EM
Herkenham
M
M
D000818:Animals; D015415:Biomarkers; D001921:Brain / Q000187:drug effects / Q000502:physiology*; D002465:Cell Movement / Q000187:drug effects; D002560:Cerebrovascular Circulation / Q000502:physiology*; D018932:Chemokine CCL2 / Q000235:genetics; D051546:Cyclooxygenase 2; D020672:I-kappa B Proteins / Q000235:genetics; D007275:Injections, Intravenous; D007276:Injections, Intraventricular; D018799:Intercellular Adhesion Molecule-1 / Q000235:genetics; D007375:Interleukin-1 / Q000008:administration & dosage* / Q000494:pharmacology; D007527:Isoenzymes / Q000235:genetics; D007962:Leukocytes / Q000502:physiology*; D008297:Male; D009457:Neuroglia / Q000502:physiology; D011451:Prostaglandin-Endoperoxide Synthases / Q000235:genetics; D012333:RNA, Messenger / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley
D015415:Biomarkers; D018932:Chemokine CCL2; D020672:I-kappa B Proteins; D007375:Interleukin-1; D007527:Isoenzymes; D012333:RNA, Messenger; D018799:Intercellular Adhesion Molecule-1; D051546:Cyclooxygenase 2; D011451:Prostaglandin-Endoperoxide Synthases