Mechanisms of opioid-mediated inhibition of human T cell receptor signaling.
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 beta-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-kappaB, 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 mu opioid receptors. Our findings contribute to the understanding of immunosuppressive side effects of morphine. Since beta-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 beta-endorphin in the physiological regulation of T cell activation.
Börner
Christine
C
Department of Pharmacology and Toxicology, University of Magdeburg, Magdeburg, Germany.
Warnick
Beate
B
Smida
Michal
M
Hartig
Roland
R
Lindquist
Jonathan A
JA
Schraven
Burkhart
B
Höllt
Volker
V
Kraus
Jürgen
J
D002478:Cells, Cultured; D006801:Humans; D007376:Interleukin-2 / Q000235:genetics; D019169:Jurkat Cells; D008213:Lymphocyte Activation; D009020:Morphine / Q000494:pharmacology*; D010766:Phosphorylation; D011948:Receptors, Antigen, T-Cell / Q000037:antagonists & inhibitors*; D017450:Receptors, Opioid, mu / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*; D014157:Transcription Factors / Q000235:genetics; D014158:Transcription, Genetic / Q000187:drug effects*; D001615:beta-Endorphin / Q000502:physiology*
D007376:Interleukin-2; D011948:Receptors, Antigen, T-Cell; D017450:Receptors, Opioid, mu; D014157:Transcription Factors; D001615:beta-Endorphin; D009020:Morphine