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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Anti-Inflammatory Agents, Non-Steroidal / pharmacology*
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Brain / drug effects
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Brain / enzymology
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Brain / metabolism
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Brain / pathology
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Cells, Cultured
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Curcumin / pharmacology*
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Cyclooxygenase 2
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DNA-Binding Proteins / antagonists & inhibitors*
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DNA-Binding Proteins / metabolism
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DNA-Binding Proteins / physiology
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Down-Regulation / drug effects
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Gene Expression Regulation / drug effects
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Inflammation / genetics
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Inflammation / metabolism
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Inflammation / prevention & control
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Interferon-gamma / antagonists & inhibitors
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Interferon-gamma / metabolism
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Interferon-gamma / pharmacology
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Intracellular Signaling Peptides and Proteins
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Isoenzymes / antagonists & inhibitors
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Isoenzymes / biosynthesis
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Janus Kinase 1
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Janus Kinase 2
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Microglia / drug effects
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Microglia / enzymology
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Microglia / metabolism
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Microglia / pathology*
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Nitric Oxide Synthase / antagonists & inhibitors
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Nitric Oxide Synthase / biosynthesis
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Nitric Oxide Synthase Type II
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Phosphorylation / drug effects
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Prostaglandin-Endoperoxide Synthases / biosynthesis
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Protein Phosphatase 2
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Protein Tyrosine Phosphatase, Non-Receptor Type 11
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Protein Tyrosine Phosphatases / metabolism*
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Protein-Tyrosine Kinases / antagonists & inhibitors*
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Protein-Tyrosine Kinases / metabolism
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Protein-Tyrosine Kinases / physiology
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Proto-Oncogene Proteins*
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Rats
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Rats, Sprague-Dawley
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Regulatory Sequences, Nucleic Acid
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SH2 Domain-Containing Protein Tyrosine Phosphatases
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STAT1 Transcription Factor
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STAT3 Transcription Factor
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Signal Transduction / drug effects*
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Signal Transduction / physiology
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Trans-Activators / antagonists & inhibitors*
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Trans-Activators / metabolism
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Trans-Activators / physiology
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Up-Regulation / drug effects
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src Homology Domains / physiology
Substances
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Anti-Inflammatory Agents, Non-Steroidal
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DNA-Binding Proteins
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Intracellular Signaling Peptides and Proteins
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Isoenzymes
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Proto-Oncogene Proteins
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STAT1 Transcription Factor
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STAT3 Transcription Factor
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Stat1 protein, rat
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Stat3 protein, rat
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Trans-Activators
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Interferon-gamma
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Nitric Oxide Synthase
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Nitric Oxide Synthase Type II
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Nos2 protein, rat
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Cyclooxygenase 2
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Prostaglandin-Endoperoxide Synthases
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Protein-Tyrosine Kinases
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Jak1 protein, rat
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Jak2 protein, rat
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Janus Kinase 1
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Janus Kinase 2
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Protein Phosphatase 2
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Protein Tyrosine Phosphatase, Non-Receptor Type 11
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Protein Tyrosine Phosphatases
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Ptpn11 protein, rat
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SH2 Domain-Containing Protein Tyrosine Phosphatases
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Curcumin