PGE2 Upregulates IL-8 Via P38MAPK-Dependent Dual-Activation of CHOP and C/EBP-β in Human Astrocytomas

• Isabella Venza

  Department of Experimental Specialized Medical and Surgical and Odontostomatology Sciences, University of Messina, Messina, Italy

• Maria Visalli

  Department ofClinical and Experimental Medicine, University of Messina, Messina, Ital

• Rosaria Oteri

  Department ofClinical and Experimental Medicine, University of Messina, Messina, Ital

• Federica Agliano

  Department of Clinical and Experimental Medicine, University of Messina, Messina, Italy

• Silvia Morabito

  Department ofClinical and Experimental Medicine, University of Messina, Messina, Ital

• Gerardo Caruso

  Neurosurgical Clinic,Department ofNeurosciences, University of Messina, Messina, Italy

• Maria Caffo

  Neurosurgical Clinic,Department ofNeurosciences, University of Messina, Messina, Italy

• Diana Teti

  Department ofClinical and Experimental Medicine, University of Messina, Messina, Ital

We previously showed that in low- as well as in high-grade astrocytomas IL-8 overexpression is triggered by prostaglandin E2 (PGE2) through the upregulation of the transcription factors CCAAT/enhancer-binding protein-β (C/EBP-β) and C/EBP homologous protein (CHOP). Here we investigated the signal transduction pathways and the molecular mechanisms underlying the PGE2-dependent IL-8 gene expression in astrocytomas. Low- and high-grade PGE2-treated astrocytoma cells were transfected with wild-type and mutated IL-8 promoter constructs in the presence of various signal transduction pathway inhibitors, and cotransfected with transcription factor overexpressing plasmids or small-interfering RNAs. p38MAPK, C/EBP-β, and CHOP phosphorylation was analyzed by Western blotting. Electrophoretic mobility shift assay and chromatin immunoprecipitation evaluated the in vitro and in vivo binding of CHOP and C/EBP-β to IL-8 promoter. The results obtained allowed us to find out the signaling pathways triggered by PGE2 and responsible for the activation of the transcription factors involved in the overproduction of IL-8 by astrocytoma. Therefore, it can be argued that the inhibition of the PGE2 downstream pathways may represent a novel therapeutic approach for the treatment of patients with astrocytoma.

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