Regulation of cyclooxygenase-2 by interferon γ and transforming growth factor α in normal human epidermal keratinocytes and squamous carcinoma cells. Role of mitogen-activated protein kinases

Hironori Matsuura, Morito Sakaue, Kotha Subbaramaiah, Hideki Kamitani, Thomas E. Eling, Andrew J. Dannenberg, Tadashi Tanabe, Hiroyasu Inoue, Jiro Arata, Anton M. Jetten

    Research output: Contribution to journalArticlepeer-review

    174 Scopus citations

    Abstract

    Treatment of normal human epidermal keratinocytes (NHEK) with interferon-γ (IFN-γ) causes a 9-fold increase in the level of cyclooxygenase-2 (COX-2) mRNA expression. Nuclear run-off assays indicate that this induction is at least partly due to increased transcription. Activation of the epidermal growth factor receptor (EGFR) signaling pathway due to the enhanced transforming growth factor α (TGFα) expression plays an important role in the induction of COX-2 by IFN-γ This is supported by the ability of TGFα to rapidly induce COX-2 and the inhibition of the IFN-γ- mediated COX-2 mRNA induction by an EGFR antibody and EGFR-selective kinase inhibitors. Deletion and mutation analysis indicates the importance of the proximal cAMP-response element/ATF site in the transcriptional control of this gene by TGFα. The increase in COX-2 mRNA by TGFα requires activation of both the extracellular signal-regulated kinase (ERK) and p38 mitogen- activated protein kinase (MAPK) pathways. Inhibition of p38 MAPK decreases the stability of COX-2 mRNA, while inhibition of MAPK/ERK kinase (MEK) does not. These results suggest that the p38 MAPK signaling pathway controls COX-2 at the level of mRNA stability, while the ERK signaling pathway regulates COX-2 at the level of transcription. In contrast to NHEK, IFN-γ and TGFα are not very effective in inducing TGFα or COX-2 expression in several squamous carcinoma cell lines, indicating alterations in both IFN-γ and TGFα response pathways.

    Original languageEnglish (US)
    Pages (from-to)29138-29148
    Number of pages11
    JournalJournal of Biological Chemistry
    Volume274
    Issue number41
    DOIs
    StatePublished - Oct 8 1999

    ASJC Scopus subject areas

    • Biochemistry
    • Molecular Biology
    • Cell Biology

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