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Inflammation Research

, Volume 68, Issue 4, pp 285–296 | Cite as

Celastrol suppresses experimental autoimmune encephalomyelitis via MAPK/SGK1-regulated mediators of autoimmune pathology

  • Shivaprasad H. Venkatesha
  • Kamal D. MoudgilEmail author
Original Research Paper
  • 48 Downloads

Abstract

Objective and design

Multiple sclerosis (MS) is a debilitating autoimmune disease involving immune dysregulation of the pathogenic T helper 17 (Th17) versus protective T regulatory (Treg) cell subsets, besides other cellular aberrations. Studies on the mechanisms underlying these changes have unraveled the involvement of mitogen-activated protein kinase (MAPK) pathway in the disease process. We describe here a gene expression- and bioinformatics-based study showing that celastrol, a natural triterpenoid, acting via MAPK pathway regulates the downstream genes encoding serum/glucocorticoid regulated kinase 1 (SGK1), which plays a vital role in Th17/Treg differentiation, and brain-derived neurotrophic factor (BDNF), which is a neurotrophic factor, thereby offering protection against experimental autoimmune encephalomyelitis (EAE) in mice.

Methods

We first tested the gene expression profile of splenocytes of EAE mice in response to the disease-related antigen, myelin oligodendrocyte glycoprotein (MOG), and then examined the effect of celastrol on that profile.

Results

Interestingly, celastrol reversed the expression of many MOG-induced genes involved in inflammation and immune pathology. The MAPK pathway involving p38MAPK and ERK was identified as one of the mediators of celastrol action. It involved suppression of SGK1 but upregulation of BDNF, which then contributed to protection against EAE.

Conclusion

Our results not only provide novel insights into disease pathogenesis, but also offer promising therapeutic targets for MS.

Keywords

Celastrol Autoimmune diseases EAE Th17/Treg balance P38 MAPK SGK1 BDNF Multiple sclerosis 

Abbreviations

AP-1

Activator protein 1

BDNF

Brain-derived neurotrophic factor

CEBPB

CCAAT enhancer binding protein β1

ERK1/2

Extracellular signal-regulated kinase ½

GSK3B

Glycogen synthase kinase 3 beta

IKBKB

Inhibitor of Nuclear factor kappa B kinase subunit beta

IRF8

Interferon regulatory factor 8

MAPK

Mitogen-activated protein kinase

MOG

Myelin oligodendrocyte glycoprotein

NFKB1

Nuclear factor kappa B subunit 1

NFKBIA

NFKB inhibitor alpha

NR3C1

Nuclear receptor subfamily 3, group C, member 1/glucocorticoid receptor

PKC

Protein kinase C

RELA

Rel-like domain-containing proteins

SGK1

Serum/glucocorticoid regulated kinase 1

SP1

Specificity protein 1

STAT4

Signal transducer and activator of transcription 4

TLR

Toll-like receptor

Notes

Acknowledgements

This work was supported in part by Grants (1R21NS082918 and R01 AT 004321) from the National Institutes of Health, Bethesda, MD and in part by VA Merit Review Award # 5 I01 BX002424 (to KDM) from the United States (U.S.) Department of Veterans Affairs [Biomedical Laboratory Research and Development Service]. We thank Jason Lees (USUHS, Bethesda) and Bodhraj Acharya (UMB) for helpful advice and discussion regarding the MOG-EAE model. We thank Rakeshchandra Reddy Meka and Steven Dudics for help with some experiments. We also thank Carol Fowler and Tom Bowen for help with the VA Research Facilities. This material is the result of work supported in part with resources and the use of facilities at the VA Maryland Health Care System, Baltimore, Maryland.

Compliance with ethical standards

Conflict of interest

The authors declare no conflict of interest. The contents do not represent the views of the U.S. Department of Veterans Affairs or the United States Government.

Supplementary material

11_2019_1219_MOESM1_ESM.pdf (570 kb)
Supplementary material 1 (PDF 569 KB)

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Copyright information

© This is a U.S. government work and not under copyright protection in the U.S.; foreign copyright protection may apply 2019

Authors and Affiliations

  • Shivaprasad H. Venkatesha
    • 1
    • 2
  • Kamal D. Moudgil
    • 1
    • 2
    • 3
    Email author
  1. 1.Department of Microbiology and ImmunologyUniversity of Maryland School of MedicineBaltimoreUSA
  2. 2.Baltimore VA Medical CenterBaltimoreUSA
  3. 3.Division of Rheumatology, Department of Microbiology and ImmunologyUniversity of Maryland School of MedicineBaltimoreUSA

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