TRANSCRIPTIONAL REGULATION OF THE HUMAN INTERLEUKIN 1β GENE BY FIBRONECTIN: ROLE OF PROTEIN KINASE C AND ACTIVATOR PROTEIN 1 (AP-1)
2000; Elsevier BV; Volume: 12; Issue: 11 Linguagem: Inglês
10.1006/cyto.2000.0759
ISSN1096-0023
AutoresJesse Roman, Jeffrey D. Ritzenthaler, Matthew J. Fenton, Susanne Roser, William Schuyler,
Tópico(s)NF-κB Signaling Pathways
ResumoInterleukin 1β (IL-1β) is a multifunctional polypeptide considered a key cytokine during inflammation. Fibronectin (FN), a matrix glycoprotein highly expressed in injured tissues, can induce expression of IL-1β in human blood monocytic cells. Herein, we explore the intracellular signals and transcriptional mechanisms responsible for IL-1β induction by FN using human promonocytic U937 cells transfected with the human IL-1β promoter connected to a reporter gene. Exposure of transfected U937s to FN resulted in increased expression of the full-length IL-1β promoter. This effect, mediated via the α5β1 integrin, was associated with activation of mitogen-activated protein kinases (MAPKs) and was abolished by pre-treatment of cells with Calphostin C, a specific inhibitor of protein kinase C (PKC) activation. Deletion analysis and co-transfection studies using consensus activator protein 1 (AP-1) oligonucleotides suggested that an AP-1 site present in the 5′ end of the IL-1β promoter was involved in the FN-induced response. Finally, electrophoretic mobility shift assays showed that FN induced binding of AP-1, but not NF-κB. Together, these experiments demonstrate that FN binding to the α5β1 integrin activates MAPK-dependent signal pathways, and results in the transcription of the IL-1β promoter in U937 cells by activating PKC and inducing AP-1.
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