Cannabinoid Receptor Type 2 Agonists Induce Transcription of the μ-Opioid Receptor Gene in Jurkat T Cells

Börner, Christine; Höllt, Volker; Kraus, Juergen

doi:10.1124/mol.105.018325

Cited by 35 publications

(33 citation statements)

References 32 publications

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“…The expression of functional opioid receptors on human T lymphocytes is induced by TNF and IL-4 (20 -22). In addition, expression of opioid receptors is also induced indirectly by drugs and stimuli, which increase the expression of TNF and IL-4, like cannabinoids (23). As demonstrated recently by our group, also anti-CD3/anti-CD28-mediated activation of human T cells induces the expression of functional opioid receptors (24).…”

mentioning

confidence: 68%

Mechanisms of Opioid-Mediated Inhibition of Human T Cell Receptor Signaling

Börner

Warnick²,

Šmída³

et al. 2009

The Journal of Immunology

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103

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Opioids are widely used for the treatment of severe pain. However, it is also known that opioids, in particular morphine, cause immunosuppression. Therefore, their use may complicate treatment of persons with an already impaired immune system, e.g., patients suffering from cancer or AIDS. We investigated the mechanisms of opioid-induced immunosuppression in primary human T lymphocytes and the human T cell line Jurkat. We demonstrated that morphine and the endogenous opioid β-endorphin inhibited the transcription of IL-2 in activated human T lymphocytes as well as the activation of the transcription factors AP-1, NFAT, and NF-κB, which transactivate IL-2. In addition, the TCR-induced calcium flux and MAPK activation were inhibited by the opioids, as well as proximal signaling events, such as the phosphorylation of the linker for activation of T cells and Zap70. A more detailed characterization of the mechanism revealed that incubation of T cells with the opioids caused a marked increase in cAMP. This in turn activated protein kinase A, which augmented the kinase activity of C-terminal Src kinase bound to phosphoprotein associated with glycosphingolipid-enrich microdomains, resulting in a further enhancement of the tonic inhibition of the leukocyte-specific protein tyrosine kinase Lck, thereby blocking the initiation of TCR signaling. These effects were mediated by μ opioid receptors. Our findings contribute to the understanding of immunosuppressive side effects of morphine. Since β-endorphin is expressed and secreted by immune effector cells, including T cells, and up-regulated in these cells by various stimuli, our data also suggest an inhibitory role for β-endorphin in the physiological regulation of T cell activation.

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confidence: 68%

Mechanisms of Opioid-Mediated Inhibition of Human T Cell Receptor Signaling

Börner

Warnick²,

Šmída³

et al. 2009

The Journal of Immunology

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103

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“…The expression of endocannabinoid receptors can be modulated by LPS or other inflammatory agents on immune cells such as T lymphocytes, for example (Jurkat T cells) (87,437). However, little is known about the molecular regulation of the genes encoding for CB receptors in immune and inflammatory cells.…”

Section: Cannabinoids Are Involved In T-cell Regulationmentioning

confidence: 99%

Neuronal Control of Skin Function: The Skin as a Neuroimmunoendocrine Organ

Roosterman¹,

Goerge

Schneider

et al. 2006

Physiological Reviews

556

521

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This review focuses on the role of the peripheral nervous system in cutaneous biology and disease. During the last few years, a modern concept of an interactive network between cutaneous nerves, the neuroendocrine axis, and the immune system has been established. We learned that neurocutaneous interactions influence a variety of physiological and pathophysiological functions, including cell growth, immunity, inflammation, pruritus, and wound healing. This interaction is mediated by primary afferent as well as autonomic nerves, which release neuromediators and activate specific receptors on many target cells in the skin. A dense network of sensory nerves releases neuropeptides, thereby modulating inflammation, cell growth, and the immune responses in the skin. Neurotrophic factors, in addition to regulating nerve growth, participate in many properties of skin function. The skin expresses a variety of neurohormone receptors coupled to heterotrimeric G proteins that are tightly involved in skin homeostasis and inflammation. This neurohormone-receptor interaction is modulated by endopeptidases, which are able to terminate neuropeptide-induced inflammatory or immune responses. Neuronal proteinase-activated receptors or transient receptor potential ion channels are recently described receptors that may have been important in regulating neurogenic inflammation, pain, and pruritus. Together, a close multidirectional interaction between neuromediators, high-affinity receptors, and regulatory proteases is critically involved to maintain tissue integrity and regulate inflammatory responses in the skin. A deeper understanding of cutaneous neuroimmunoendocrinology may help to develop new strategies for the treatment of several skin diseases.

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“…In the cells, the stimulus-induced transcription factors then bind to the excess of decoy oligonucleotides rather than to the gene's regulatory elements, which results in attenuation of the induction of the gene. The specificity of the decoy oligonucleotides for the desired transcription factors and that of the respective mutated negative control oligonucleotides had been shown in previous reports from our group (Börner et al, 2006(Börner et al, , 2007. Decoy oligonucleotides directed against STAT6 completely abolished IL-4-mediated induction of CB1 (Fig.…”

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confidence: 99%

“…STAT factors are specialized factors that respond to cytokines and growth factors. Most transcriptional effects of IL-4 are mediated by the transcription factors STAT6 and GATA3 (Hou et al, 1994;Kraus et al, 2003b;Börner et al, 2006). Experiments using decoy oligonucleotides excluded the involvement of GATA3 in the IL-4-mediated up-regulation of CB1 but clearly established the role of STAT6 (Fig.…”

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confidence: 99%

“…Among other mechanisms, such as the inhibition of the expression of the T helper cell type 1 cytokine interferon-␥, cannabinoids lead to the induction of IL-4, which is a key factor for the T-helper cell type 2 differentiation and its maintenance (Curfs et al, 1997;O'Garra and Arai, 2000). This cannabinoid-induced induction of IL-4 is mediated by CB2 receptors, which are abundantly expressed in resting T lymphocytes (Börner et al, 2006). IL-4 then in turn induces genes, which further promote T-helper cell type 2 development and, as reported now, the CB1 receptor gene.…”

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confidence: 99%

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Analysis of Promoter Regions Regulating Basal and Interleukin-4-Inducible Expression of the Human CB1 Receptor Gene in T Lymphocytes

Börner

Bedini²,

Höllt³

et al. 2007

Mol Pharmacol

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The majority of effects of cannabinoids are mediated by the two receptors CB1 and CB2. In addition to neuronal cells, CB1 receptors are expressed in T lymphocytes, in which they are involved in cannabinoid-induced T helper cell biasing. Although basally expressed only weakly in T cells, CB1 receptors are up-regulated in these cells by stimuli such as cannabinoids themselves. This effect is mediated by interleukin-4. In this study, we investigated basal and interleukin-4-inducible expression of the CB1 gene in T lymphocytes. In a promoter analysis, two regions [nucleotides (nts) Ϫ3086 to Ϫ2490 and nts Ϫ1950 to Ϫ1653] were identified, which suppress basal transcription of the gene in Jurkat T cells, whereas the region between nts Ϫ648 and Ϫ559 enhanced basal

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Cannabinoid Receptor Type 2 Agonists Induce Transcription of the μ-Opioid Receptor Gene in Jurkat T Cells

Cited by 35 publications

References 32 publications

Mechanisms of Opioid-Mediated Inhibition of Human T Cell Receptor Signaling

Mechanisms of Opioid-Mediated Inhibition of Human T Cell Receptor Signaling

Neuronal Control of Skin Function: The Skin as a Neuroimmunoendocrine Organ

Analysis of Promoter Regions Regulating Basal and Interleukin-4-Inducible Expression of the Human CB1 Receptor Gene in T Lymphocytes

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