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Mechanisms of Opioid-Mediated Inhibition of Human T Cell Receptor Signaling¹

Christine Börner^*, Beate Warnick^*, Michal Smida, Roland Hartig, Jonathan A. Lindquist, Burkhart Schraven, Volker Höllt^* and Jürgen Kraus^*,2

*Department of Pharmacology and Toxicology and Department of Molecular and Clinical Immunology, University of Magdeburg, Magdeburg, Germany

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-B, 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.

² Address correspondence and reprint requests to Dr. Jürgen Kraus, Department of Pharmacology and Toxicology, University of Magdeburg, 44 Leipzigerstrasse, 39120 Magdeburg, Germany. E-mail address: juergen.kraus{at}med.ovgu.de

¹ This work was supported by a research grant from the government of the state of Sachsen-Anhalt (N2/ND: Physiologie und Pathophysiologie signalübertragender Netzwerke im Immun- und Nervensystem) provided to V.H. and B.S. and a grant from the Deutsche Forschungsgemeinschaft (KR 1740/10-1) to J.K.