Interferon-beta prevents cytokine-induced neutrophil infiltration and attenuates blood-brain barrier disruption.
Inflammation can contribute to brain injury, such as that resulting from ischemia or trauma. The authors have previously shown that the cytokine interferon-beta (IFN-beta) affords protection against ischemic brain injury, which was associated with a diminished infiltration of neutrophils and a reduction in blood-brain barrier (BBB) disruption. The goal of the current study was to directly assess the effects of IFN-beta on neutrophil infiltration, with the use of an in vivo assay of neutrophil infiltration with relevance to ischemic brain injury. Intrastriatal injection of recombinant rat cytokine-induced neutrophil chemoattractant-1, a member of the interleukin-8 family (1 microg in 1 microl), triggered massive infiltration of neutrophils and extensive BBB disruption 6 hours later, as measured using immunofluorescence microscopy and magnetic resonance imaging in the rat, respectively. Depleting the animals of neutrophils before interleukin-8 injection prevented BBB disruption. Treatment with IFN-beta (5 x 106 U/kg) almost completely prevented neutrophil infiltration and attenuated BBB damage. Gelatinase zymography showed matrix metalloproteinase-9 expression in the ipsilateral striatum after interleukin-8 injection. Both neutrophil depletion and IFN-beta treatment downregulated matrix metalloproteinase-9. IFN-beta has already been approved for human use as a treatment for the chronic inflammatory disorder multiple sclerosis. The potential value of IFN-beta as a treatment that can attenuate acute brain inflammation is considered.
Veldhuis
Wouter B
WB
Image Sciences Institute, University Medical Center Utrecht, Utrecht, The Netherlands. veldhuis@invivonmr.uu.nl
Floris
Sarah
S
van der Meide
Peter H
PH
Vos
Ine M P
IM
de Vries
Helga E
HE
Dijkstra
Christien D
CD
Bär
Peter R
PR
Nicolay
Klaas
K
D000818:Animals; D001810:Blood Volume; D001812:Blood-Brain Barrier / Q000187:drug effects; D001921:Brain / Q000033:anatomy & histology / Q000502:physiology; D002560:Cerebrovascular Circulation; D004730:Endothelium, Vascular / Q000166:cytology / Q000378:metabolism; D006439:Hemodynamics; D006801:Humans; D018799:Intercellular Adhesion Molecule-1 / Q000378:metabolism; D016899:Interferon-beta / Q000276:immunology / Q000494:pharmacology*; D016209:Interleukin-8 / Q000276:immunology / Q000494:pharmacology*; D008279:Magnetic Resonance Imaging; D008297:Male; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D009474:Neurons / Q000166:cytology / Q000378:metabolism; D020556:Neutrophil Infiltration; D009504:Neutrophils / Q000276:immunology / Q000502:physiology*; D051381:Rats; D011916:Rats, Inbred F344; D011994:Recombinant Proteins / Q000494:pharmacology
D016209:Interleukin-8; D011994:Recombinant Proteins; D018799:Intercellular Adhesion Molecule-1; D016899:Interferon-beta; D020780:Matrix Metalloproteinase 9