Monocyte 15-lipoxygenase gene expression requires ERK1/2 MAPK activity

A Bhattacharjee, A Mulya, S Pal, B Roy… - The Journal of …, 2010 - journals.aai.org
A Bhattacharjee, A Mulya, S Pal, B Roy, GM Feldman, MK Cathcart
The Journal of Immunology, 2010journals.aai.org
IL-13 induces profound expression of 15-lipoxygenase (15-LO) in primary human
monocytes. Our studies have defined the functional IL-13R complex, association of Jaks with
the receptor components, and the tyrosine phosphorylation of several Stat molecules in
response to IL-13. Furthermore, we identified both p38MAPK and protein kinase Cδ as
critical regulators of 15-LO expression. In this study, we report an ERK1/2-dependent
signaling cascade that regulates IL-13–mediated 15-LO gene expression. We show the …
Abstract
IL-13 induces profound expression of 15-lipoxygenase (15-LO) in primary human monocytes. Our studies have defined the functional IL-13R complex, association of Jaks with the receptor components, and the tyrosine phosphorylation of several Stat molecules in response to IL-13. Furthermore, we identified both p38MAPK and protein kinase Cδ as critical regulators of 15-LO expression. In this study, we report an ERK1/2-dependent signaling cascade that regulates IL-13–mediated 15-LO gene expression. We show the rapid phosphorylation/activation of ERK1/2 upon IL-13 exposure. Our results indicate that Tyk2 kinase is required for the activation of ERK1/2, which is independent of the Jak2, p38MAPK, and protein kinase Cδ pathways, suggesting bifurcating parallel regulatory pathways downstream of the receptor. To investigate the signaling mechanisms associated with the ERK1/2-dependent expression of 15-LO, we explored the involvement of transcription factors, with predicted binding sites in the 15-LO promoter, in this process including Elk1, early growth response-1 (Egr-1), and CREB. Our findings indicate that IL-13 induces Egr-1 nuclear accumulation and CREB serine phosphorylation and that both are markedly attenuated by inhibition of ERK1/2 activity. We further show that ERK1/2 activity is required for both Egr-1 and CREB DNA binding to their cognate sequences identified within the 15-LO promoter. Furthermore, by transfecting monocytes with the decoy oligodeoxyribonucleotides specific for Egr-1 and CREB, we discovered that Egr-1 and CREB are directly involved in regulating 15-LO gene expression. These studies characterize an important regulatory role for ERK1/2 in mediating IL-13–induced monocyte 15-LO expression via the transcription factors Egr-1 and CREB.
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