The Role of Nuclear Factor κB in Tumor Necrosis Factor-Regulated Transcription of the Human μ-Opioid Receptor Gene

Abstract

Opioids and their receptors are key players in a cross-talk between the nervous and immune systems. For example, the endogenous opioid system is activated during inflammation as a physiological feedback mechanism to attenuate inflammatory pain. Herein, we report that in primary human T lymphocytes, Raji B cells, U937 monocytes, primary human polymorphonuclear leukocytes, and mature dendritic cells, the proinflammatory cytokine tumor necrosis factor induced -opioid receptor gene transcription. Transcriptional induction of the gene in immune cells was mediated via tumor necrosis factor receptor type 2. Using selective in vivo disruption of possibly involved transcription factors with decoy oligonucleotides, nuclear factor-B was identified as the factor responsible for induction of the gene in immune cells, whereas activator protein-1 was found to be uninvolved. Nuclear factor-B also mediates upregulation of -opioid receptors in neuronal cells stimulated with tumor necrosis factor. Among six putative nuclear factor-B binding sites on the -opioid receptor gene promoter, three cis-active elements at nt Ϫ2174, Ϫ557, and Ϫ207 were identified using transfection experiments of reporter gene constructs, electrophoretic mobility shift assays, and in vivo binding studies with decoy oligonucleotides. An allelic variation within the Ϫ557 element significantly reduced its trans-activating potency, which may affect regulation of the -opioid receptor gene in persons carrying this mutation. This study suggests a regulatory function of tumor necrosis factor in opioid-mediated processes in neuronal and immune cells, with possible impact on the complex of inflammation-induced analgesia.

Regulation of pain sensitivity in experimental osteoarthritis by the endogenous peripheral opioid system

“…It has been shown that proinflammatory cytokines and nerve growth factor can induce -opioid receptor expression in inflammatory conditions (23,25,26) and may be involved in the transient increase in opiate receptors in OA. One could envisage that proinflammatory cytokines produced locally in the joint act on the nerves to induce receptor expression and a transient analgesia.…”

Nuclear Factor κB Signaling in Opioid Functions and Receptor Gene Expression

“…It has been reported that the proinflammatory cytokine TNF induced mor gene transcription in various immune cells, including human T lymphocytes, leukocytes, and mature dendritic cells (Kraus et al 2003). NF-κB was identified to be responsible for TNF-induced mor gene expression through three NF-κB cis elements on the human mor promoter (Kraus et al 2003).…”

“…In the previous section, we reviewed the involvement of NF-κB signaling in opioid functions both in immune cells and neuronal cells. This section focuses on the involvement of NF-κB signaling in the transcriptional regulation of opioid receptor genes (Chen et al 2006;Kraus et al 2003;Park and Wei 2003;Wang et al 2004). …”

“…Moreover, NF-κB is either directly or indirectly involved in several GPCRmediated downstream signaling pathways, including the cAMP/protein kinase A (PKA)/ cAMP response element binding protein (CREB), PI3K/Akt/inhibitor of IκB kinase complex (IKK), and MAPK/IKK pathways (Ye 2001). Many research laboratories have reported that NF-κB may be involved in opiate-meditated immune functions (Azuma and Ohura 2002;Carr et al 1995;Kraus et al 2003;Roy et al 1998b;Wang et al 2003;Welters et al 2000a). More recently, NF-κB has been found to be involved in the transcriptional regulation of mor gene expression in primary immune cells (Kraus et al 2003) and dor gene expression during nerve growth factor (NGF)-induced differentiation of neuronal cells (Chen et al 2006).…”

“…Many research laboratories have reported that NF-κB may be involved in opiate-meditated immune functions (Azuma and Ohura 2002;Carr et al 1995;Kraus et al 2003;Roy et al 1998b;Wang et al 2003;Welters et al 2000a). More recently, NF-κB has been found to be involved in the transcriptional regulation of mor gene expression in primary immune cells (Kraus et al 2003) and dor gene expression during nerve growth factor (NGF)-induced differentiation of neuronal cells (Chen et al 2006). NF-κB may also be involved in kor gene expression in P19 cells (Law et al 2004).…”