Journal
CURRENT MOLECULAR MEDICINE
Volume 15, Issue 4, Pages 401-410Publisher
BENTHAM SCIENCE PUBL LTD
DOI: 10.2174/1566524015666150505160743
Keywords
Arthritis; celastrol; inflammation; lupus; neutrophil extracellular trap
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Funding
- NATIONAL INSTITUTE OF ARTHRITIS AND MUSCULOSKELETAL AND SKIN DISEASES [R01AR059351] Funding Source: NIH RePORTER
- NIAMS NIH HHS [R01 AR059351] Funding Source: Medline
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Neutrophil extracellular traps (NETs) are web-like structures released by activated neutrophils. Recent studies suggest that NETs play an active role in driving autoimmunity and tissue injury in diseases including rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE). The purpose of this study was to investigate if celastrol, a triterpenoid compound, can inhibit NET formation induced by inflammatory stimuli associated with RA and SLE. We found that celastrol can completely inhibit neutrophil oxidative burst and NET formation induced by tumor necrosis factor alpha (TNF alpha) with an IC50 of 0.34 mu M and by ovalbumin: anti-ovalbumin immune complexes (Ova IC) with an IC50 of 1.53 mu M. Celastrol also completely inhibited neutrophil oxidative burst and NET formation induced by immunoglobulin G (IgG) purified from RA and SLE patient sera. Further investigating into the mechanisms, we found that celastrol treatment downregulated the activation of spleen tyrosine kinase (SYK) and the concomitant phosphorylation of mitogen-activated protein kinase kinase (MAPKK/MEK), extracellular-signal-regulated kinase (ERK), and NF kappa B inhibitor alpha (I kappa B alpha), as well as citrullination of histones. Our data reveals that celastrol potently inhibits neutrophil oxidative burst and NET formation induced by different inflammatory stimuli, possibly through downregulating the SYK-MEK-ERK-NF kappa B signaling cascade. These results suggest that celastrol may have therapeutic potentials for the treatment of inflammatory and autoimmune diseases involving neutrophils and NETs.
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