Permeability of the blood–brain and blood–spinal cord barriers to interferons
Introduction
Cytokines can exert a variety of effects on the central nervous system (CNS). Peripheral administration of interferon γ (IFNγ) induces major histocompatibility complex (MHC) I antigen expression in both microglia and endothelial cells (Xu and Ling, 1994) and MHC II antigen expression in microglia, especially in the subcortical white matter and circumventricular region of newborn rats (Xu and Ling, 1995). It has not been determined whether IFNγ causes these central changes directly by passage across the blood–brain and blood–spinal cord barriers (BBB).
Tumor necrosis factor α (TNFα) is another proinflammatory cytokine with similar effects as IFNγ in increasing autoimmunity and enhancing inflammation (Pan et al., 1997b). In an animal model for multiple sclerosis, experimental autoimmune encephalomyelitis (EAE), TNFα can modulate the course of the disorder and inhibitors of TNFα decrease autoimmune demyelination (Monastra et al., 1993; Selmaj et al., 1991). TNFα receptors are present in the brain (Kinouchi et al., 1991) where there is a saturable transport system for TNFα from blood (Gutierrez et al., 1993).
In contrast to the proinflammatory effects of IFNγ and TNFα, IFNα has immunosuppressive effects (Panitch, 1992). Peripherally injected IFNα can be found in cerebrospinal fluid (Habif et al., 1975) and the receptor for IFNα has been localized to microglial cells in the brain (Yamada and Yamanaka, 1995). The greatest number of binding sites (Bmax) have been found in the hypothalamus and the least in the spinal cord (Janicki, 1992). It is possible that the CNS side-effects of IFNα as an anti-tumor agent (Quesada et al., 1986) could be related to its passage into the CNS.
The availability of cytokines to the spinal cord, although not well studied, may be significant in several aspects. First, the permeability of the spinal cord could be greater than that of the brain for cytokines so that their entry into the distal spinal cord could be involved in the development of immune and inflammatory processes there (Daniel et al., 1985). Second, in disorders such as EAE, disruption of the barrier is more prominent and occurs earlier in the distal spinal cord (Daniel et al., 1981; Juhler et al., 1984). Third, neurotrophic effects of cytokines, such as stimulation of synthesis of nerve growth factor by TNFα (Chao et al., 1995), may contribute to spinal cord regeneration.
Using sensitive techniques, we compared the permeability of the BBB to these three cytokines in the brain and the three main regions of the spinal cord.
Section snippets
Radioactive labeling and purification
Recombinant murine IFNα and IFNγ (CHO produced and tested for endotoxin, GIBCO BRL, Gaithersburg) and murine TNFα (R&D Systems, Minneapolis) were labeled with by the enzymobead method (Biorad, Richmond). The labeled products were separated on a column of Sephadex G-10 and eluted with chloride-free phosphate buffer solution (PBS). The specific activities of the I-IFNs and I-TNFα were about 80 Ci/g.
Human serum albumin (Alb) was labeled with c (Tc-Alb) with the kit from Medi+Physics
Tissue/serum ratios of IFNα, IFNγ, and TNFα
The correlations between the tissue/serum ratios and exposure time for each iodinated cytokine were statistically significant in all regions, except for I-IFNγ in the lumbosacral spinal cord (p<0.07), as shown in Table 1.
In each region examined, there was a variation in the permeation of the three cytokines across the BBB. The most permeable was IFNα and the least permeable was IFNγ.
For each cytokine, the cervical spinal cord was the most permeable whereas the brain was the least. The
Discussion
In these experiments we examined the permeability of the blood–brain barrier and blood–spinal cord barrier to IFNγ, IFNα and TNFα, the amount of penetration into brain parenchyma relative to an association with the vascular space, the stability of the transported cytokine and the saturability of the transport system.
There were regional differences in the permeabilities of the blood–spinal cord barriers to the three cytokines. The cervical and lumbosacral spinal cord had higher tissue/serum
Acknowledgements
We are grateful to Melita B. Fasold for help with graphics and editing and to Dr. Jeannine A. Majde for intellectual encouragement. Supported by ONR (N00014-92-J-1384), VA Rehab and VA Merit Review.
References (26)
- Audus, K.L. and Borchardt, R.T. (1987) Bovine brain microvessel endothelial cell monolayers as a model system for the...
- Blasberg, R.G., Fenstermacher, J.D. and Patlak, C.S. (1983) Transport of α-aminoisobutyric acid across brain capillary...
- Broadwell, R.D., Balin, B.J. and Salcman, M. (1988) Transcytotic pathway of blood-borne protein through the blood–brain...
- Broadwell, R.D. and Sofroniew, M.V. (1993) Serum proteins bypass the blood–brain fluid barriers for extracellular entry...
- Chao, C.C., Hu, S., Sheng, W.S. and Peterson, P.K. (1995) Tumor necrosis factor-alpha production by human fetal...
- Daniel, P.M., Lam, D.K.C. and Pratt, O.E. (1981) Changes in the effectiveness of the blood–brain and blood–spinal cord...
- Daniel, P.M., Lam, D.K.C. and Pratt, O.E. (1985) Comparison of the vascular permeability of the brain and the spinal...
- Gutierrez, E.G., Banks, W.A. and Kastin, A.J. (1993) Murine tumor necrosis factor alpha is transported from blood to...
- Habif, D.V., Lipton, K. and Cantell, K. (1975) Interferon crosses blood–cerebrospinal fluid barrier in monkeys. Proc....
- Janicki, P.K. (1992) Binding of human alpha-interferon in the brain tissue membranes of rat. Res. Commun. Chem. Pathol....
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