Inhibition of NF-κB by Opioids in T Cells

Abstract

Opioids potently inhibit a number of physiological and pathophysiological effects such as pain and inflammation in the brain and the periphery. One of the targets of opioids mediating such effects is the proinflammatory transcription factor NF-κB. In neuronal cells, opioids inhibit this factor by inducing I-κB independently on calcium, involving the opioid-mediated activation of the transcription factor AP-1. However, when and how precisely NF-κB is modulated by opioids in T cells are unknown. By using the TNF-triggered, NF-κB–mediated induction of IL-8 mRNA in primary human T cells and Jurkat T cells, in this study we show that opioids inhibit NF-κB in T cells as well, but that the underlying mechanisms are different from those observed in neuronal cells. We found that stimulation of the T cells with opioids resulted in a significant inhibition of the TNF-triggered ubiquitination and degradation of I-κB. Additionally, an opioid-mediated induction of the deubiquitinating enzyme ubiquitin-specific protease 15 was observed, which is known to inhibit the NF-κB pathway by stabilizing I-κB. The induction of ubiquitin-specific protease 15 was dependent on calcium and the transcription factor NFAT. Activation of AP-1 and induction of I-κB in response to the opioids were not observed in the T cells. These results indicate that μ opioid receptors, which mediate the effects in both cell types, might be coupled to different effector cascades in the different cell types, which may then result in cell type–specific effects of the drugs.

Transgenerational modification of hippocampus TNF-α and S100B levels in the offspring of rats chronically exposed to morphine during adolescence

“…Chronic administration of opioids induces functional interactions between the immune and nervous systems (41)(42)(43)(44). Some factors of the immune system (such as TNF-α, IL-1β, IL-6, and NF-KB) show modifications due to chronic morphine exposure, and these modifications affect hippocampus function (45,46).…”

The activation of μ‐opioid receptor potentiates LPS‐induced NF‐kB promoting an inflammatory phenotype in microglia

“…In particular, PKCε −/− murine macrophages were found to display an impairment in LPS‐induced IkB‐α degradation and consecutive NF‐kB activation . Furthermore, it has been reported that NF‐kB activity in different cell types is either increased or decreased in response to opioids.…”

Analgesia in mice with experimental meningitis reduces pain without altering immune parameters

“…Buprenorphine, compared to other opioids, was shown to have the least immune-modulatory effects (Al-Hashimi et al, 2013). In a recent study, Borner and Kraus demonstrated that opioids inhibited NF-κB, a crucial transcription factor in T cell activation, in T cells (Borner and Kraus, 2013). The LCMV-induced meningitis model is strictly dependent on cytotoxic T cells (Kang and McGavern, 2008).…”