MORPHINE INHIBITS TRANSCRIPTIONAL ACTIVATION OF IL-2 IN MOUSE THYMOCYTES

Chronic treatment of mice with morphine affects the proliferation, dif ferentiation, and function of immune cells. In the present study, we i nvestigated the mechanism by which morphine inhibits phytohemagglutini n (PHA)/interleukin-1 (IL-1)-induced thymocyte proliferation. When com pared to control cultures, morphine-treated thymocytes showed decrease d steady-state levels of bioactive IL-2 and IL-2 mRNA. The reduced IL- 2 concentration and reduced transcript levels correlated well with a d ecreased rate of synthesis of IL-2 mRNA as determined by nuclear runof f assays. Subsequent studies showed that morphine treatment affected t ranscriptional 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 de creased 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 con sensus oligonucleotide showed significantly decreased levels of AP-1-p rotein complex formation in nuclear extracts prepared hom morphine-tre ated cells. These studies demonstrate for the first time that opioid a lkaloids such as morphine can impair mitogen-lymphokine-activated thym ocyte proliferation by interfering with transcriptional activation of the IL-2 gene. (C) 1997 Academic Press.