title: Morphine inhibits transcriptional activation of IL-2 in mouse thymocytes.
abstract: Chronic treatment of mice with morphine affects the proliferation, differentiation, and function of immune cells. In the present study, we investigated the mechanism by which morphine inhibits phytohemagglutinin (PHA)/interleukin-1 (IL-1)-induced thymocyte proliferation. When compared to control cultures, morphine-treated thymocytes showed decreased steady-state levels of bioactive IL-2 and IL-2 mRNA. The reduced IL-2 concentration and reduced transcript levels correlated well with a decreased rate of synthesis of IL-2 mRNA as determined by nuclear runoff assays. Subsequent studies showed that morphine treatment affected transcriptional control elements of the IL-2 promoter by inhibiting the synthesis of a specific trans-activating nuclear factor, c-Fos. c-Fos mRNA levels measured by semiquantitative RT-PCR were significantly decreased in thymocytes following treatment with morphine and activation with PHA and IL-1. Under identical conditions, c-Jun mRNA levels were not altered. Electrophoretic mobility shift studies with the AP-1 consensus oligonucleotide showed significantly decreased levels of AP-1-protein complex formation in nuclear extracts prepared from morphine-treated cells. These studies demonstrate for the first time that opioid alkaloids such as morphine can impair mitogen-lymphokine-activated thymocyte proliferation by interfering with transcriptional activation of the IL-2 gene.
authors.affiliation: Department of Pharmacology, University of Minnesota, Minneapolis 55455, USA. royxx002@gold.tc.umn.edu
authors.forename: S
authors.initials: S
authors.lastname: Roy
authors.forename: R B
authors.initials: RB
authors.lastname: Chapin
authors.forename: K J
authors.initials: KJ
authors.lastname: Cain
authors.forename: R G
authors.initials: RG
authors.lastname: Charboneau
authors.forename: S
authors.initials: S
authors.lastname: Ramakrishnan
authors.forename: R A
authors.initials: RA
authors.lastname: Barke
mesh_terms: D000818:Animals; D002455:Cell Division / Q000187:drug effects; D005786:Gene Expression Regulation / Q000187:drug effects; D007376:Interleukin-2 / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D009020:Morphine / Q000494:pharmacology*; D016760:Proto-Oncogene Proteins c-fos / Q000235:genetics; D016755:Proto-Oncogene Proteins c-jun / Q000235:genetics; D012333:RNA, Messenger; D013950:Thymus Gland / Q000166:cytology; D018808:Transcription Factor AP-1 / Q000378:metabolism; D015533:Transcriptional Activation / Q000187:drug effects*
chemical_list: D007376:Interleukin-2; D016760:Proto-Oncogene Proteins c-fos; D016755:Proto-Oncogene Proteins c-jun; D012333:RNA, Messenger; D018808:Transcription Factor AP-1; D009020:Morphine