Protein kinase D, ubiquitin and proteasome pathways are involved in adenosine receptor-stimulated NR4A expression in myeloid cells

Adenosine is a purine nucleoside pivotal for homeostasis in cells and tissues. Stimulation of the adenosine receptors (AR) has been shown to regulate nuclear orphan receptor 4A (NR4A1-3) family, resulting attenuation hyper-inflammatory responses myeloid cells. The NR4A1-3 are early immediate response genes transcriptional regulators cell tissue homeostasis. signal transduction mechanism(s) how AR-stimulation promotes NR4A expression unknown focus this study. We confirm that stable analogue, 5′-N-Ethylcarboxamidoadenosine (NECA), enhance THP-1 Pharmacological approaches identified protein kinase D (PKD) mediates AR-stimulated reveals no involvement PKA nor PKC. role NF-κB, principal regulator cells, was examined as possible downstream PKD. Utilising BAY11-7082 MG-132, inhibitors respective ubiquitin proteasome pathways essential NF-κB activation, suggested prospective or more specifically signalling via IKKα/β. However, biological interventional studies using overexpression IκBα MEF lacking IKKα IKKβ (IKKα/β−/-) revealed pathway not utilised mediating expression. Thus, study contributes mechanistic insight into AR modulates receptors, inflammatory