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InterLeukin-10 In Multiple Sclerosis

  1. InterLeukin-4 and InterLeukin-10 modulate nuclear factor kappaB activity and Nitric Oxide Synthase-2 expression in Theiler's Virus-infected Brain Astrocytes
    J NeuroChem 2002 Jun;81(6):1242-52

  2. InterLeukin-10 in the Brain
    Crit Rev Immunol 2001;21(5):427-49

  3. Genetic variation at position -1082 of InterLeukin 10 (IL-10) promotor and the outcome of Multiple Sclerosis
    J NeuroImmunol 2000 Apr 3;104(1):98-100

  4. Levels of InterLeukin-10-Secreting blood MonoNuclear Cells are low in untreated Multiple Sclerosis but Augmented during Interferon-ß-1b treatment
    Scand J Immunol 1999 May;49(5):554-561

  5. Role of Th1 and Th2 cells in AutoImmune DeMyelinating Disease
    Braz J Med Biol Res 1998 Jan;31(1):55-60

  6. Low Serum InterLeukin-10 levels in Multiple Sclerosis: further evidence for decreased systemic ImmunoSuppression?
    J Neurol 1996 Jan;243(1):13-7




#1

InterLeukin-4 And InterLeukin-10 Modulate Nuclear Factor kappaB Activity And Nitric Oxide Synthase-2 Expression In Theiler's Virus-Infected Brain Astrocytes

Molina-Holgado E, Arevalo-Martin A, Castrillo A, Bosca L, Vela JM, Guaza C.
J NeuroChem 2002 Jun;81(6):1242-52
Instituto Cajal, Consejo Superior de Investigaciones Cientificas, Department of Neural Plasticity, Madrid, Spain
PMID# 12068072
Abstract

In Brain Astrocytes, nuclear factor kappaB (NF-kappaB) is activated by stimuli that produce cellular stress causing the expression of Genes involved in defence, including the inducible Nitric Oxide synthase (NOS-2).

Theiler's Murine Encephalomyelitis Virus (TMEV) induces a persistent CNS infection and chronic Immune-mediated DeMyelination, similar to human Multiple Sclerosis.

The Cytokines InterLeukin-4 (IL-4) and IL-10 inhibit the expression of proinflammatory Cytokines, counteracting the inflammatory process.

Our study reports that infection of cultured Astrocytes with TMEV resulted in a time-dependent phosphorylation of IkappaBalpha, degradation of IkappaBalpha and IkappaBbeta, activation of NF-kappaB and expression of NOS-2.

The proteasome inhibitor MG-132 blocked TMEV-induced nitrite accumulation, NOS-2 mRNA expression and phospho-IkappaBalpha degradation, suggesting NF-kappaB-dependent NOS-2 expression.

Pretreatment of Astrocytes with IL-4 or IL-10 decreased p65 nuclear translocation, NF-kappaB binding activity and NOS-2 transcription. IL-4 and IL-10 caused an accumulation of IkappaBalpha in TMEV-infected Astrocytes without affecting IkappaBbeta levels.

The IkappaB kinase activity and the degradation rate of both IkappaBs were not modified by either Cytokine, suggesting de novo synthesis of IkappaBalpha. Indeed, IL-4 or IL-10 up-regulated IkappaBalpha mRNA levels after TMEV infection.

Therefore, the accumulation of IkappaBalpha might impair the translocation of the NF-kappaB to the Nucleus, mediating the inhibition of NF-kappaB activity.

Overall, these data suggest a novel mechanism of action of IL-4 and IL-10, which abrogates NOS-2 expression in viral-infected Glial Cells.



#2

InterLeukin-10 In The Brain

Strle K, Zhou JH, Shen WH, Broussard SR, Johnson RW, Freund GG, Dantzer R, Kelley KW.
Crit Rev Immunol 2001;21(5):427-49
University of Illinois, College of Medicine, Department of Animal Sciences, Urbana 61801, USA
PMID# 11942558
Abstract

InterLeukin-10 (IL-10) is synthesized in the Central Nervous System (CNS) and acts to limit clinical symptoms of Stroke, Multiple Sclerosis, Alzheimer's Disease, Meningitis, and the behavioral changes that occur during Bacterial Infections.

Expression of IL-10 is elevated during the course of most major diseases in the CNS and promotes survival of Neurons and all Glial Cells in the Brain by blocking the effects of ProApoptotic Cytokines and by promoting expression of cell survival signals.

Stimulation of IL-10 receptors regulates numerous life- or death-signaling pathways including: Jak1/Stat3, PI 3-kinase, MAPK, SOCS, and NF-kappaB.

Ultimately promoting cell survival, by inhibiting both Ligand- and Mitochondrial-induced Apoptotic Pathways, IL-10 also limits inflammation in the Brain.

    It does so by three major pathways:
    1. Reducing synthesis of ProInflammatory Cytokines
    2. Suppressing Cytokine Receptor expression
    3. Inhibiting Receptor activation

Finally, IL-10 induces Anergy in Brain-infiltrating T-Cells by inhibiting cell signaling through the Costimulatory CD28-CD80/86 pathway.

The multiple functions of IL-10 in the Brain will create new and intriguing vistas that will promote a better understanding of NeuroDegenerative Diseases.

These discoveries could lead to development of innovative approaches for the use of AntiInflammatory Cytokines in major debilitating diseases of the CNS.



#3

Genetic Variation Of InterLeukin 10 (IL10) And The Outcome Of Multiple Sclerosis

Maurer M, Kruse N, Giess R, Toyka KV, Rieckmann P
J NeuroImmunol 2000 Apr 3;104(1):98-100
Bayerische Julius Maximilians Universitat, Dept of Neurology, Josef-Schneider-Str. 11 97080, Wurzburg, Germany
PMID# 10683520
Abstract

InterLeukin-10 is a potent ImmunoModulatory Cytokine with possible implications for the PathoGenesis of Multiple Sclerosis.

Increased IL-10 mRNA expression is associated with stable disease.

The InterLeukin-10 Gene is highly polymorphic and certain HaploTypes result in differential InterLeukin-10 expression.

The presence of Guanine instead of Adenine at position -1082 in the IL-10 promotor was shown to result in a higher IL10 production.

We analyzed this diallelic PolyMorphism in patients with Multiple Sclerosis but did not find any association between a certain -1082 IL-10 GenoType and susceptibility to or severity of Multiple Sclerosis.



#4

Levels Of InterLeukin-10-MonoNuclear Cells Are Low In Untreated Multiple Sclerosis But Augmented During Interferon-ß-1b Treatment

Ozenci V, Kouwenhoven M, Huang Y, Xiao B, Kivisakk P, Fredrikson S, Link H
Scand J Immunol 1999 May;49(5):554-561
Karolinska Institute, Division of Neurology, Huddinge Univ Hospital, Stockholm, Sweden
PMID# 10320650
Abstract

The Cytokine InterLeukin-10 (IL-10) has Immune response down-regulatory properties, which include suppression of the synthesis of pro-inflammatory Cytokines such as Interferon-gamma (IFN-gamma) and of Major Histocompatibility Complex (MHC) Class II expression on Monocytes.

To further elucidate the involvement of IL-10 in Multiple Sclerosis (MS), an enzyme-linked Immunospot assay was adopted to enumerate IL-10-secreting MonoNuclear Cells (MNC) in peripheral blood.

IFN-gamma secreting MNC were detected in parallel. Levels of IL-10-secreting cells were lower in patients with MS compared with Other Neurological Diseases (OND) and healthy subjects.

This difference was seen only in patients with untreated MS, and not in those undergoing treatment with IFN-ß-1b.

No differences were observed when subgrouping the patients with MS regarding clinical phase (Exacerbation, Remission, Secondary Progression), duration of MS or Disability Status.

Levels of IFN-gamma-secreting blood MNC did not differ in patients with MS, irrespective of treatment with IFN-ß-1b, compared with OND and healthy subjects.

Patients with MS, but not the two groups of controls, had elevated numbers of IL-10- and IFN-gamma-secreting cells upon stimulation with MBP compared with culture in the absence of Antigen.

The data suggest that IL-10 is decreased in MS and that treatment resulting in its up-regulation beneficially influence the Disease.



#5

Role Of Th1 & Th2 Cells In AutoImmune DeMyelinating Disease

Nagelkerken L
Braz J Med Biol Res 1998 Jan;31(1):55-60
TNO Prevention and Health, Division of Immunological and Infectious Diseases, Leiden, The Netherlands
PMID# 9686179; UI# 98350796
Abstract

Evidence is accumulating that Th1 cells play an important role in the development of Multiple Sclerosis (MS) and Experimental Allergic EncephaloMyelitis (EAE), whereas Th2 Cells contribute to recovery from disease.

A major determinant in the development of Th1 and Th2 Cells is the type of Antigen Presenting Cell (APC) involved and its functional characteristics, e.g., the production of InterLeukin-12.

Therefore, modulation of APC might interfere with the development of Th1 type responses and as such be beneficial for MS and EAE.

The potential of Cytokines, in particular InterLeukin-10, and GlucoCorticoids to exert a selective effect on APC, and as a consequence to affect the Th1-Th2 balance in EAE, is discussed.



#6

Low Serum InterLeukin-10 Levels In Multiple Sclerosis: Further Evidence For Decreased Systemic ImmunoSuppression?

Salmaggi A, Dufour A, Eoli M, Corsini E, La Mantia L, Massa G, Nespolo A, Milanese C
J Neurol 1996 Jan;243(1):13-7
Istituto Nazionale Neurologico C. Besta, Milano, Italy
PMID# 8869381; UI# 97023021
Abstract

Serum InterLeukin-10 (IL-10) levels were assessed in patients with Multiple Sclerosis who were either in a stable or active clinical condition. The levels were compared with values in healthy controls.

Lower IL-10 levels than in controls were seen in Multiple Sclerosis patients, regardless of clinical disease activity. Low IL-10 levels were also seen in patients with Systemic Lupus Erythematosus.

No clear-cut relationships emerged between IL-10 levels and those of Tumor Necrosis Factor-alpha and Transforming Growth Factor ß, or between IL-10 and Lymphocyte subsets in peripheral blood.



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