Regulation of cyclooxygenase-2 by interferon gamma and transforming growthfactor alpha in normal human epidermal keratinocytes and squamous carcinoma cells - Role of mitogen-activated protein kinases
H. Matsuura et al., Regulation of cyclooxygenase-2 by interferon gamma and transforming growthfactor alpha in normal human epidermal keratinocytes and squamous carcinoma cells - Role of mitogen-activated protein kinases, J BIOL CHEM, 274(41), 1999, pp. 29138-29148
Treatment of normal human epidermal keratinocytes (NHEK) with interferon-ga
mma (IFN-gamma) causes a 9-fold increase in the level of cyclooxggenase-2 (
COX-2) mRNA expression. Nuclear run-off assays indicate that this induction
is at least partly due to increased transcription. Activation of the epide
rmal growth factor receptor (EGFR) signaling pathway due to the enhanced tr
ansforming growth factor alpha (TGF alpha) expression plays an important ro
le in the induction of COX-2 by IFN-gamma. This is supported by the ability
of TGF alpha to rapidly induce COX-2 and the inhibition of the IFN-gamma-m
ediated 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 t
his gene by TGF alpha. The increase in COX-2 mRNA by TGF alpha requires act
ivation of both the extracellular signal-regulated kinase (ERK) and p38 mit
ogen-activated protein kinase (MAPK) pathways. Inhibition of p38 MAPK decre
ases the stability of COX-2 mRNA, while inhibition of MAPK/ERK kinase (MEK)
does not. These results suggest that the p38 MAPK signaling pathway contro
ls COX-2 at the level of mRNA stability, while the ERK signaling pathway re
gulates COX-2 at the level of transcription. In contrast to NHEK IFN-gamma
and TGF alpha are not very effective in inducing TGF alpha or COX-2 express
ion in several squamous carcinoma cell lines, indicating alterations in bot
h IFN-gamma and TGF alpha response pathways.