Effects of dexamethasone on microglial activation in vivo: selective downregulation of major histocompatibility complex class II expression in regenerating facial nucleus

doi:10.1016/0165-5728(91)90119-R

Journal of Neuroimmunology

Volume 34, Issues 2–3, November 1991, Pages 99-108

https://doi.org/10.1016/0165-5728(91)90119-R Get rights and content

Abstract

Following axotomy of the facial nerve microglial cells in the facial nucleus become activated, proliferate, and newly express class I and class II major histocompatibility complex (MHC) antigens. Dexamethasone treatment, starting 2 days prior to axotomy at 1 mg/kg/day, selectively inhibited axotomy-induced MHC class II expression on microglial and perivascular cells. In contrast, MHC class I expression was not significantly affected, nor was the expression of other microglial activation markers and the light microscopic morphology of activated microglia. A recently suggested inducer of MHC expression in rat nervous tissue, neuronal gamma interferon-like immunoreactive material, was also unaffected, as was glial fibrillary acidic protein immunoreactivity as a marker for concomitant astroglial activation.

The differential effects of the drug suggest the presence of distinct regulatory pathways for different aspects of microglial activation. Inhibition of class II expression on activated microglia might be one mechanism how glucocorticoids act in the suppression of neuroinflammatory disease.

References (47)

C. Bolton et al.
The effects of the anti-glucocorticoid RU 38486 on steroid-mediated suppression of experimental allergic encephalomyelitis (EAE) in the Lewis rat
Life Sci.
(1989)
J. Cammermeyer
The effect of cortisone treatment and reoperation on reactive changes in the facial nucleus after axotomy
Brain Res.
(1975)
M.B. Graeber et al.
Microglial cells but not astrocytes undergo mitosis following rat facial nerve axotomy
Neurosci. Lett.
(1988)
M.B. Graeber et al.
New expression of myelomonocytic antigens by microglia and perivascular cells following lethal motor neuron injury
J. Neuroimmunol.
(1990)
R. Kiefer et al.
Gamma interferon-like immunoreactivity in the rat nervous system
Neuroscience
(1990)
J. Maehlen et al.
Local enhancement of major histocompatibility complex (MHC) class I and II expression and cell infiltration in experimental allergic encephalomyelitis around axotomized motor neurons
J. Neuroimmunol.
(1989)
N.R. Nichols et al.
Messenger RNA for glial fibrillary acidic protein is decreased in rat brain following acute and chronic corticosterone treatment
Mol. Brain Res.
(1990)
J.P. O'Callaghan et al.
Glucocorticoids regulate the concentration of glial fibrillary acidic protein throughout the brain
Brain Res.
(1989)
V.H. Perry et al.
Macrophages and microglia in the nervous system
Trends Neurosci.
(1988)
M. Sawada et al.
Production of tumor necrosis factor-alpha by microglia and astrocytes in culture
Brain Res.
(1989)

W.J. Streit et al.

Peripheral nerve lesion produces increased levels of major histocompatibility complex antigens in the central nervous system

J. Neuroimmunol.

(1989)

W.J. Streit et al.

Expression of Ia antigen on perivascular and microglial cells after sublethal and lethal motor neuron injury

Exp. Neurol.

(1989)

A. Suzumura et al.

MHC antigen expression on bulk isolated macrophage-microglia from newborn mouse brain: induction of Ia antigen expression by γ-interferon

J. Neuroimmunol.

(1987)

B. Thorens et al.

Phagocytosis and inflammatory stimuli induce GM-CSF mRNA in macrophages through posttranscriptional regulation

Cell

(1987)

A.F. Williams et al.

Analysis of cell surfaces by xenogeneic myeloma-hybrid antibodies: differentiation antigens of rat lymphocytes

Cell

(1977)

H. Akiyama et al.

Major histocompatibility complex antigen expression on rat microglia following epidural kainic acid lesions

J. Neurosci. Res.

(1988)

M. Aronsson et al.

Localization of glucocorticoid receptor mRNA in the male rat brain by in situ hybridization

S.K. Arya et al.

Dexamethasone-mediated inhibition of human T cell growth factor and γ-interferon messenger RNA

J. Immunol.

(1984)

B. Beutler et al.

Control of cachectin (tumor necrosis factor) synthesis: mechanisms of endotoxin resistance

Science

(1986)

K. Blinzinger et al.

Displacement of synaptic terminals from regenerating motoneurons by microglial cells

Z. Zellforsch.

(1968)

Y.-C. Chou et al.

Characterization of glucocorticoid type II receptors in neuronal and glial cultures from rat brain

J. Neuroendocrinol.

(1990)

T.R. Cupps et al.

Corticosteroid-mediated immunoregulation in man

Immunol. Rev.

(1982)

D. Fertsch-Ruggio et al.

Induction of macrophage Ia antigen expression by rIFN-γ and downregulation by IFN-α/β and dexamethasone are regulated transcriptionally

J. Immunol.

(1988)

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Effects of dexamethasone on microglial activation in vivo: selective downregulation of major histocompatibility complex class II expression in regenerating facial nucleus

Abstract

Life Sci.

Brain Res.

Neurosci. Lett.

J. Neuroimmunol.

Neuroscience

J. Neuroimmunol.

Mol. Brain Res.

Brain Res.

Trends Neurosci.

Brain Res.

J. Neuroimmunol.

Exp. Neurol.

J. Neuroimmunol.

Cell

Cell

Major histocompatibility complex antigen expression on rat microglia following epidural kainic acid lesions

J. Neurosci. Res.

Localization of glucocorticoid receptor mRNA in the male rat brain by in situ hybridization

Dexamethasone-mediated inhibition of human T cell growth factor and γ-interferon messenger RNA

J. Immunol.

Control of cachectin (tumor necrosis factor) synthesis: mechanisms of endotoxin resistance

Science

Displacement of synaptic terminals from regenerating motoneurons by microglial cells

Z. Zellforsch.

Characterization of glucocorticoid type II receptors in neuronal and glial cultures from rat brain

J. Neuroendocrinol.

Corticosteroid-mediated immunoregulation in man

Immunol. Rev.

Induction of macrophage Ia antigen expression by rIFN-γ and downregulation by IFN-α/β and dexamethasone are regulated transcriptionally

J. Immunol.