Inhibition of NF-κB by opioids in T cells.
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.
Department of Pharmacology and Toxicology, University of Magdeburg, 39120 Magdeburg, Germany.
Christine
C
Börner
Jürgen
J
Kraus
D000701:Analgesics, Opioid / Q000378:metabolism*; D002118:Calcium / Q000378:metabolism*; D002478:Cells, Cultured; D006801:Humans; D051550:I-kappa B Kinase / Q000378:metabolism*; D007249:Inflammation / Q000188:drug therapy; D016209:Interleukin-8 / Q000235:genetics; D019169:Jurkat Cells; D016328:NF-kappa B / Q000037:antagonists & inhibitors*; D050778:NFATC Transcription Factors / Q000378:metabolism; D034622:RNA Interference; D012333:RNA, Messenger / Q000096:biosynthesis; D034741:RNA, Small Interfering; D017450:Receptors, Opioid, mu / Q000378:metabolism*; D013601:T-Lymphocytes / Q000378:metabolism; D018808:Transcription Factor AP-1 / Q000378:metabolism; D048069:Tumor Necrosis Factors / Q000378:metabolism; D064570:Ubiquitin-Specific Proteases / Q000235:genetics / Q000378:metabolism; D054875:Ubiquitination
D000701:Analgesics, Opioid; D016209:Interleukin-8; D016328:NF-kappa B; D050778:NFATC Transcription Factors; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D017450:Receptors, Opioid, mu; D018808:Transcription Factor AP-1; D048069:Tumor Necrosis Factors; D051550:I-kappa B Kinase; C579226:USP15 protein, human; D064570:Ubiquitin-Specific Proteases; D002118:Calcium