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OtherPROSTAGLANDINS, LEUKOTRIENES AND OTHER EICOSANOIDS

Tyrosine Phosphatase-Dependent/Tyrosine Kinase-Independent Induction of Nuclear Factor-κB by Tumor Necrosis Factor-α: Effects on Prostaglandin Endoperoxide Synthase-2 mRNA Accumulation

Keyvan Mahboubi, Wilson Young and Nicholas R. Ferreri
Journal of Pharmacology and Experimental Therapeutics May 1998, 285 (2) 862-868;
Keyvan Mahboubi
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Wilson Young
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Nicholas R. Ferreri
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Abstract

We previously have demonstrated that tumor necrosis factor-α (TNF-α) increases prostaglandin endoperoxide synthase-2 (PGHS-2) mRNA accumulation and tyrosine phosphorylation in the fibrosarcoma cell line, MCA-101. Tyrosine kinase inhibitor, genistein, and tyrosine phosphatase inhibitor, phenylarsine oxide (PAO), blocked TNF-α-mediated induction of PGHS-2 mRNA in these cells. Because the PGHS-2 promoter has a nuclear factor-κB (NF-κB) binding motif, which is important for PGHS-2 gene transcription in some cell types, we have evaluated the effects of tyrosine kinase inhibitors and PAO on TNF-α-induced NF-κB activation. TNF-α (1 nM) rapidly induced translocation of NF-κB, an event accompanied by degradation of inhibitory protein IκB-α. N-tosyl-l-phenylalanine chloromethyl ketone (TPCK), a serine protease inhibitor, inhibited IκB-α degradation and NF-κB activation in response to TNF-α in a dose-dependent manner (25, 50, 100 μM). TPCK also inhibited PGHS-2 mRNA accumulation. These data suggest that NF-κB contributed to PGHS-2 mRNA accumulation in MCA-101 cells stimulated with TNF-α. PAO (2.4 μM) completely abolished activation of NF-κB and degradation of IκB-α induced by TNF-α at a concentration that blocked PGHS-2 mRNA accumulation. However, four tyrosine kinase inhibitors, genistein, tyrphostin 47, herbimycin A and erbstatin, failed to block translocation of NF-κB and degradation of IκB-α. These data demonstrate that tyrosine kinase pathways are not required for TNF-α-induced NF-κB activation in MCA-101 cells and suggest that signaling via these pathways mediates TNF-α-induced PGHS-2 mRNA accumulation via an NF-κB-independent mechanism. Moreover, an upstream tyrosine phosphatase pathway may mediate PGHS-2 mRNA accumulation by TNF-α via an NF-κB-dependent mechanism.

Footnotes

  • Send reprint requests to: Dr. Keyvan Mahboubi, Department of Pharmacology, New York Medical College, Valhalla, NY 10595.

  • Abbreviations:
    PGHS-2
    prostaglandin endoperoxide synthase-2
    NF-κB
    nuclear factor-κB
    MCA
    methylcholanthrene
    TNF-α
    tumor necrosis factor-α
    TBST
    tris buffer saline tween
    SDS
    sodium dodecyl sulfate
    PBS
    phosphate-buffered saline
    EMSA
    electrophoresis mobility shift assay
    C/EBPβ
    CCAAT/enhancer binding protein β
    CRE
    cyclic AMP response element
    PMSF
    phenylmethylsulfonyl fluoride
    PAO
    phenylarsine oxide
    PTKs
    protein tyrosine kinases
    PTPase(s)
    protein tyrosine phosphatases
    TPCK
    N-tosyl-l-phenylalanine chloromethyl ketone
    MTT
    3-(4,5-dimethylthiazol-2-yl)2,5-diphenyltetrazolium
    PAGE
    polyacrylamide gel electrophoresis
    HEPES
    N-2-hydroxyethylpiperazine-N′-2-ethanesulfonic acid
    EDTA
    ethylenediaminetetraacetic acid
    DTT
    dithiothreitol
    SSC
    standard saline citrate
    • Received April 8, 1997.
    • Accepted January 27, 1998.
  • The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics
Vol. 285, Issue 2
1 May 1998
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OtherPROSTAGLANDINS, LEUKOTRIENES AND OTHER EICOSANOIDS

Tyrosine Phosphatase-Dependent/Tyrosine Kinase-Independent Induction of Nuclear Factor-κB by Tumor Necrosis Factor-α: Effects on Prostaglandin Endoperoxide Synthase-2 mRNA Accumulation

Keyvan Mahboubi, Wilson Young and Nicholas R. Ferreri
Journal of Pharmacology and Experimental Therapeutics May 1, 1998, 285 (2) 862-868;

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OtherPROSTAGLANDINS, LEUKOTRIENES AND OTHER EICOSANOIDS

Tyrosine Phosphatase-Dependent/Tyrosine Kinase-Independent Induction of Nuclear Factor-κB by Tumor Necrosis Factor-α: Effects on Prostaglandin Endoperoxide Synthase-2 mRNA Accumulation

Keyvan Mahboubi, Wilson Young and Nicholas R. Ferreri
Journal of Pharmacology and Experimental Therapeutics May 1, 1998, 285 (2) 862-868;
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