A reduction in serum glucocorticoids provokes experimental allergic encephalomyelitis

Reder, Anthony T.; Thapar, Manjula; Jensen, Mark A.

doi:10.1212/wnl.44.12.2289

Cited by 44 publications

(23 citation statements)

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“…For example, Lewis rats with relatively reduced HPA reactivity compared with Fischer rats are more susceptible to autoimmune disease than Fischer rats (8,9). Administration of GC inhibits autoimmune disease in Lewis rats, whereas administration of the GR antagonist RU486 increases the severity of disease in these animals (8,31). In addition, enhanced plasma CORT levels may favor the production of Th2 cytokines over Th1 cytokines (25,32,33), thus reducing the severity of EAE (34).…”

Section: Discussionmentioning

confidence: 99%

Neonatal Dexamethasone Treatment Increases Susceptibility to Experimental Autoimmune Disease in Adult Rats

Bakker

Kavelaars²,

Kamphuis

et al. 2000

The Journal of Immunology

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Major concern has emerged about the possible long term adverse effects of glucocorticoid treatment, which is frequently used for the prevention of chronic lung disease in preterm infants. Here we show that neonatal glucocorticoid treatment of rats increases the severity (p ≤ 0.01) and incidence (p ≤ 0.01) of the inflammatory autoimmune disease experimental autoimmune encephalomyelitis in adult life. In search of possible mechanisms responsible for the increased susceptibility to experimental autoimmune encephalomyelitis, we investigated the reactivity of the hypothalamo-pituitary-adrenal axis and of immune cells in adult rats after neonatal glucocorticoid treatment. We observed that neonatal glucocorticoid treatment reduces the corticosterone response after an LPS challenge in adult rats (p ≤ 0.001). Interestingly, LPS-stimulated macrophages of glucocorticoid-treated rats produce less TNF-α and IL-1β in adult life than control rats (p < 0.05). In addition, splenocytes obtained from adult rats express increased mRNA levels of the proinflammatory cytokines IFN-γ (p < 0.01) and TNF-β (p < 0.05) after neonatal glucocorticoid treatment. Apparently, neonatal glucocorticoid treatment has permanent programming effects on endocrine as well as immune functioning in adult life. In view of the frequent clinical application of glucocorticoids to preterm infants, our data demonstrate that neonatal glucocorticoid treatment may be a risk factor for the development of (auto)immune disease in man.

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Section: Discussionmentioning

confidence: 99%

Neonatal Dexamethasone Treatment Increases Susceptibility to Experimental Autoimmune Disease in Adult Rats

Bakker

Kavelaars²,

Kamphuis

et al. 2000

The Journal of Immunology

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“…GCs can lead to severe relapses (Reder et al, 1994), which can be prevented by slowly reducing GCs instead of a sudden withdrawal. This led to the current treatment protocol used in MS patients that includes an oral taper of methylprednisolone (Beck et al, 1992).…”

Section: Side Effects Of Glucocorticoid Therapymentioning

confidence: 99%

“…This could be circumvented by a combination therapy with erythropoietin where the neurodegenerative effects were reduced (Diem et al, 2005). Moreover, it was observed that the fast withdrawal of GCs can lead to severe relapses (Reder et al, 1994), which can be prevented by slowly reducing GCs instead of a sudden withdrawal. This led to the current treatment protocol used in MS patients that includes an oral taper of methylprednisolone (Beck et al, 1992).…”

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confidence: 99%

Glucocorticoids in the control of neuroinflammation

Tischner

Reichardt

2007

Molecular and Cellular Endocrinology

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Glucocorticoids are a class of steroid hormones that are endowed with profound antiinflammatory and immunosuppressive activities. Endogenous glucocorticoids are key players in the modulation of the immune system and establish an endocrine basis of many inflammatory diseases. In addition, synthetic glucocorticoids are amongst the most commonly prescribed drugs worldwide for the treatment of autoimmune disorders. In this review we summarize our present knowledge on the mechanisms by which glucocorticoids impact on multiple sclerosis (MS), a highly prevalent neuroinflammatory disease, and its animal model experimental autoimmune encephalomyelitis (EAE). In spite of the new methodologies that have become available during recent years, we are still far from a comprehensive picture of the mechanism by which glucocorticoids control neuroinflammation. Keywords: Glucocorticoids; Multiple Sclerosis; Experimental AutoimmuneEncephalomyelitis; Apoptosis; Blood-brain barrier Page 2 of 33A c c e p t e d M a n u s c r i p t -3 IntroductionGlucocorticoids (GCs) are a class of steroid hormones that are commonly used to treat acute and chronic inflammatory disorders (Tuckermann et al., 2005). They exert most of their functions by binding to the glucocorticoid receptor (GR), which controls gene expression and signalling cascades through genomic as we ll as non-genomic mechanisms. By this means, GCs modulate the survival, differentiation, migration and various effector functions of leukocytes and other cell types and thereby impact both, innate and adaptive immunity. W hilst GCs administered at pharmacological concentrations are considered purely immunosuppressive, fluctuations in the levels of endogenous GCs, e.g. during stress, result in more complex immunomodulatory effects (Elenkov and Chrousos, 1999).One major application of GCs is the treatment of neuroinflammatory disorders, in particular multiple sclerosis (MS), the most prevalent chronic autoimmune disease of the central nervous system (CNS) in the Western world (Noseworthy et al., 2000). MS is characterized by infiltrating autoreactive T-cells in the CNS that initiate aninflammatory cascade involving leukocytes and humoral components (Sospedra and Martin, 2005). This causes demyelination and axonal loss, which eventually leads to severe functional deficits. While GCs have no positive effect on the long-term prognosis of MS, optic neuritis and other acute relapses are widely treated with high doses of methylprednisolone (Milligan et al., 1987). Still, such a therapy may lead to severe complications or incomplete recovery. Furthermore, it is known that the course of MS is influenced by the level of endogenous GCs (Elenkov and Chrousos, 1999). Women in the third trimester of pregnancy and Cushing syndrome patients often experience remission of the disease. This is explained by a polarization of the immune system towards T H 2 dominated responses as a consequence of increased Page 3 of 33A c c e p t e d M a n u s c r i p t -4 cortisol synthesis. Thus, fluctuations in G...

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“…Stress-induced elevation of endogenous glucocorticoid protects from EAE. Exogenously administered glucocorticoid hormones, which are known to alleviate human autoimmune diseases, can suppress EAE in mice as well (3)(4)(5), and a similar beneficial response is observed in multiple sclerosis (6,7). In contrast, elimination of glucocorticoid by adrenalectomy or antagonist administration worsens disease (3,8).…”

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confidence: 92%

Corticotropin-Releasing Hormone Contributes to the Peripheral Inflammatory Response in Experimental Autoimmune Encephalomyelitis

Benou

Wang

Imitola

et al. 2005

The Journal of Immunology

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Peripheral corticotropin-releasing hormone (CRH) is thought to have proinflammatory effects. We used the model of experimental autoimmune encephalomyelitis (EAE) to study the role of CRH in an immune-mediated disease. We showed that CRH-deficient mice are resistant to EAE, with a decrease in clinical score as well as decreased cellular infiltration in the CNS. Furthermore, Ag-specific responses of primed T cells as well as anti-CD3/anti-CD28 TCR costimulation were decreased in crh−/− mice with decreased production of Th1 cytokines and increased production of Th2 cytokines. Wild-type mice treated in vivo with a CRH antagonist showed a decrease in IFN-γ production by primed T cells in vitro. This effect of CRH is independent of its ability to increase corticosterone production, because adrenalectomized wild-type mice had similar disease course and severity as control mice. We found that IκBα phosphorylation induced by TCR cross-linking was decreased in crh−/− T cells. We conclude that peripheral CRH exerts a proinflammatory effect in EAE with a selective increase in Th1-type responses. These findings have implications for the treatment of Th1-mediated diseases such as multiple sclerosis.

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A reduction in serum glucocorticoids provokes experimental allergic encephalomyelitis

Cited by 44 publications

References 0 publications

Neonatal Dexamethasone Treatment Increases Susceptibility to Experimental Autoimmune Disease in Adult Rats

Neonatal Dexamethasone Treatment Increases Susceptibility to Experimental Autoimmune Disease in Adult Rats

Glucocorticoids in the control of neuroinflammation

Corticotropin-Releasing Hormone Contributes to the Peripheral Inflammatory Response in Experimental Autoimmune Encephalomyelitis

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