IL-1β regulates blood-brain barrier permeability via reactivation of the hypoxia-angiogenesis program

Azeb Tadesse Argaw, Yueting Zhang, Brian J. Snyder, Meng Liang Zhao, Natalya Kopp, Sunhee C. Lee, Cedric S. Raine, Celia F. Brosnan, Gareth R. John

Research output: Contribution to journalArticle

177 Citations (Scopus)

Abstract

Loss of blood-brain barrier (BBB) integrity is believed to be an early and significant event in lesion pathogenesis in the inflammatory demyelinating disease multiple sclerosis (MS), and understanding mechanisms involved may lead to novel therapeutic avenues for this disorder. Well-differentiated endothelium forms the basis of the BBB, while astrocytes control the balance between barrier stability and permeability via production of factors that restrict or promote vessel plasticity. In this study, we report that the proinflammatory cytokine IL-1β, which is prominently expressed in active MS lesions, causes a shift in the expression of these factors to favor plasticity and permeability. The transcription factor, hypoxia inducible factor-1 (HIF-1), plays a significant role in this switch. Using a microarray-based approach, we found that in human astrocytes, IL-1β induced the expression of genes favoring vessel plasticity, including HIF-1α and its target, vascular endothelial growth factor-A (VEGF-A). Demonstrating relevance to MS, we showed that HIF-1α and VEGF-A were expressed by reactive astrocytes in active MS lesions, while the VEGF receptor VEGFR2/flk-1 localized to endothelium and IL-1 to microglia/macrophages. Suggesting functional significance, we found that expression of IL-1β in the brain induced astrocytic expression of HIF-1α, VEGF-A, and BBB permeability. In addition, we confirmed VEGF-A to be a potent inducer of BBB permeability and angiogenesis, and demonstrated the importance of IL-1β-induced HIF-1α in its regulation. These results suggest that IL-1β contributes to BBB permeability in MS via reactivation of the HIF-VEGF axis. This pathway may represent a potential therapeutic target to restrict lesion formation.

Original languageEnglish (US)
Pages (from-to)5574-5584
Number of pages11
JournalJournal of Immunology
Volume177
Issue number8
StatePublished - Oct 15 2006

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Hypoxia-Inducible Factor 1
Blood-Brain Barrier
Interleukin-1
Permeability
Vascular Endothelial Growth Factor A
Multiple Sclerosis
Astrocytes
Endothelium
Vascular Endothelial Growth Factor Receptor-2
Microglia
Demyelinating Diseases
Hypoxia
Transcription Factors
Macrophages
Cytokines
Gene Expression
Brain
Therapeutics

ASJC Scopus subject areas

  • Immunology

Cite this

Argaw, A. T., Zhang, Y., Snyder, B. J., Zhao, M. L., Kopp, N., Lee, S. C., ... John, G. R. (2006). IL-1β regulates blood-brain barrier permeability via reactivation of the hypoxia-angiogenesis program. Journal of Immunology, 177(8), 5574-5584.

IL-1β regulates blood-brain barrier permeability via reactivation of the hypoxia-angiogenesis program. / Argaw, Azeb Tadesse; Zhang, Yueting; Snyder, Brian J.; Zhao, Meng Liang; Kopp, Natalya; Lee, Sunhee C.; Raine, Cedric S.; Brosnan, Celia F.; John, Gareth R.

In: Journal of Immunology, Vol. 177, No. 8, 15.10.2006, p. 5574-5584.

Research output: Contribution to journalArticle

Argaw, AT, Zhang, Y, Snyder, BJ, Zhao, ML, Kopp, N, Lee, SC, Raine, CS, Brosnan, CF & John, GR 2006, 'IL-1β regulates blood-brain barrier permeability via reactivation of the hypoxia-angiogenesis program', Journal of Immunology, vol. 177, no. 8, pp. 5574-5584.
Argaw AT, Zhang Y, Snyder BJ, Zhao ML, Kopp N, Lee SC et al. IL-1β regulates blood-brain barrier permeability via reactivation of the hypoxia-angiogenesis program. Journal of Immunology. 2006 Oct 15;177(8):5574-5584.
Argaw, Azeb Tadesse ; Zhang, Yueting ; Snyder, Brian J. ; Zhao, Meng Liang ; Kopp, Natalya ; Lee, Sunhee C. ; Raine, Cedric S. ; Brosnan, Celia F. ; John, Gareth R. / IL-1β regulates blood-brain barrier permeability via reactivation of the hypoxia-angiogenesis program. In: Journal of Immunology. 2006 ; Vol. 177, No. 8. pp. 5574-5584.
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abstract = "Loss of blood-brain barrier (BBB) integrity is believed to be an early and significant event in lesion pathogenesis in the inflammatory demyelinating disease multiple sclerosis (MS), and understanding mechanisms involved may lead to novel therapeutic avenues for this disorder. Well-differentiated endothelium forms the basis of the BBB, while astrocytes control the balance between barrier stability and permeability via production of factors that restrict or promote vessel plasticity. In this study, we report that the proinflammatory cytokine IL-1β, which is prominently expressed in active MS lesions, causes a shift in the expression of these factors to favor plasticity and permeability. The transcription factor, hypoxia inducible factor-1 (HIF-1), plays a significant role in this switch. Using a microarray-based approach, we found that in human astrocytes, IL-1β induced the expression of genes favoring vessel plasticity, including HIF-1α and its target, vascular endothelial growth factor-A (VEGF-A). Demonstrating relevance to MS, we showed that HIF-1α and VEGF-A were expressed by reactive astrocytes in active MS lesions, while the VEGF receptor VEGFR2/flk-1 localized to endothelium and IL-1 to microglia/macrophages. Suggesting functional significance, we found that expression of IL-1β in the brain induced astrocytic expression of HIF-1α, VEGF-A, and BBB permeability. In addition, we confirmed VEGF-A to be a potent inducer of BBB permeability and angiogenesis, and demonstrated the importance of IL-1β-induced HIF-1α in its regulation. These results suggest that IL-1β contributes to BBB permeability in MS via reactivation of the HIF-VEGF axis. This pathway may represent a potential therapeutic target to restrict lesion formation.",
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AU - Snyder, Brian J.

AU - Zhao, Meng Liang

AU - Kopp, Natalya

AU - Lee, Sunhee C.

AU - Raine, Cedric S.

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