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Curcumin suppresses Janus kinase-STAT inflammatory signaling through activation of Src homology 2 domain-containing tyrosine phosphatase 2 in brain microglia.

Authors
Kim, HY; Park, EJ; Joe, EH; Jou, I
Citation
Journal of immunology (Baltimore, Md. : 1950), 171(11):6072-6079, 2003
Journal Title
Journal of immunology (Baltimore, Md. : 1950)
ISSN
0022-17671550-6606
Abstract
Curcumin has been strongly implicated as an anti-inflammatory agent, but the precise mechanisms of its action are largely unknown. In this study, we show that the inhibitory action of curcumin on Janus kinase (JAK)-STAT signaling can contribute to its anti-inflammatory activity in the brain. In both rat primary microglia and murine BV2 microglial cells, curcumin effectively suppressed the ganglioside-, LPS-, or IFN-gamma-stimulated induction of cyclooxygenase-2 and inducible NO synthase, important enzymes that mediate inflammatory processes. These anti-inflammatory effects appear to be due, at least in part, to the suppression of the JAK-STAT inflammatory signaling cascade. Curcumin markedly inhibited the phosphorylation of STAT1 and 3 as well as JAK1 and 2 in microglia activated with gangliosides, LPS, or IFN-gamma. Curcumin consistently suppressed not only NF binding to IFN-gamma-activated sequence/IFN-stimulated regulatory element, but also the expression of inflammation-associated genes, including ICAM-1 and monocyte chemoattractant protein 1, whose promoters contain STAT-binding elements. We further show that activation of Src homology 2 domain-containing protein tyrosine phosphatases (SHP)-2, a negative regulator of JAK activity, is likely to be one of the mechanisms underlying the curcumin-mediated inhibition of JAK-STAT signaling. Treatment of microglial cells with curcumin led to an increase in phosphorylation and association with JAK1/2 of SHP-2, which inhibit the initiation of JAK-STAT inflammatory signaling in activated microglia. Taken together, these data suggest curcumin suppresses JAK-STAT signaling via activation of SHP-2, thus attenuating inflammatory response of brain microglial cells.
MeSH terms
AnimalsAnti-Inflammatory Agents, Non-Steroidal/pharmacology*Brain/drug effectsBrain/enzymologyBrain/metabolismBrain/pathologyCells, CulturedCurcumin/pharmacology*Cyclooxygenase 2DNA-Binding Proteins/antagonists & inhibitors*DNA-Binding Proteins/metabolismDNA-Binding Proteins/physiologyDown-Regulation/drug effectsGene Expression Regulation/drug effectsInflammation/geneticsInflammation/metabolismInflammation/prevention & controlInterferon-gamma/antagonists & inhibitorsInterferon-gamma/metabolismInterferon-gamma/pharmacologyIntracellular Signaling Peptides and ProteinsIsoenzymes/antagonists & inhibitorsIsoenzymes/biosynthesisJanus Kinase 1Janus Kinase 2Microglia/drug effectsMicroglia/enzymologyMicroglia/metabolismMicroglia/pathology*Nitric Oxide Synthase/antagonists & inhibitorsNitric Oxide Synthase/biosynthesisNitric Oxide Synthase Type IIPhosphorylation/drug effectsProstaglandin-Endoperoxide Synthases/biosynthesisProtein Phosphatase 2Protein Tyrosine Phosphatase, Non-Receptor Type 11Protein Tyrosine Phosphatases/metabolism*Protein-Tyrosine Kinases/antagonists & inhibitors*Protein-Tyrosine Kinases/metabolismProtein-Tyrosine Kinases/physiologyProto-Oncogene Proteins*RatsRats, Sprague-DawleyRegulatory Sequences, Nucleic AcidSH2 Domain-Containing Protein Tyrosine PhosphatasesSTAT1 Transcription FactorSTAT3 Transcription FactorSignal Transduction/drug effects*Signal Transduction/physiologyTrans-Activators/antagonists & inhibitors*Trans-Activators/metabolismTrans-Activators/physiologyUp-Regulation/drug effectssrc Homology Domains/physiology
PMID
14634121
Appears in Collections:
Journal Papers > School of Medicine / Graduate School of Medicine > Pharmacology
Journal Papers > Research Organization > Chronic Inflammatory Disease Research Center
AJOU Authors
박, 은정조, 은혜주, 일로
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