Chronic morphine treatment differentiates T helper cells to Th2 effector cells by modulating transcription factors GATA 3 and T-bet.
Chronic morphine treatment in animal models has been shown to alter a number of immune parameters including suppression of cellular immunity. T helper cell differentiation into Th2 effector cell may be a major contributing factor to impaired cellular immunity following chronic drug abuse. We had previously shown that chronic morphine treatment in vivo and in vitro decreases IL-2 and IFNgamma (Th1) protein levels and increases IL-4 and IL-5 (Th2) protein levels in a time-dependent manner. In addition in this paper, we show that chronic morphine treatment resulted in a decrease in IFNgamma and IL-2 mRNA and an increase in IL-4 and IL-5 mRNA accumulation in murine splenocytes. Furthermore, chronic morphine treatment inhibited IFNgamma promoter activity and increased IL-4 promoter activity in respective promoter transfected primary T cells. In addition, we also demonstrate that chronic morphine treatment resulted in an increase in GATA 3 binding to DNA consensus elements in electromobility shift assays and an increase in GATA 3 protein and mRNA levels. In contrast, chronic morphine treatment resulted in a decrease in T-bet mRNA levels. From these data, we conclude that chronic morphine treatment differentiates T helper cell to Th2 effector cells by modulating key master switches that results in committing T helper cell to a Th2 phenotype.
Roy
Sabita
S
Department of Surgery, University of Minnesota, Minneapolis Veterans Affairs Medical Center, Minneapolis, MN 55455, USA. royxx002@umn.edu
Wang
Jinghua
J
Gupta
Sumandeep
S
Charboneau
Richard
R
Loh
Horace H
HH
Barke
Roderick A
RA
D000818:Animals; D000906:Antibodies / Q000494:pharmacology; D015153:Blotting, Western / Q000379:methods; D018106:CD28 Antigens / Q000276:immunology; D017252:CD3 Complex / Q000276:immunology; D002452:Cell Count / Q000379:methods; D002454:Cell Differentiation / Q000187:drug effects; D002478:Cells, Cultured; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D004247:DNA / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D024202:Electrophoretic Mobility Shift Assay / Q000379:methods; D050990:GATA3 Transcription Factor; D051379:Mice; D018345:Mice, Knockout; D009020:Morphine / Q000494:pharmacology*; D009294:Narcotics / Q000494:pharmacology*; D011401:Promoter Regions, Genetic / Q000187:drug effects / Q000502:physiology; D011485:Protein Binding; D012333:RNA, Messenger / Q000096:biosynthesis / Q000187:drug effects; D020133:Reverse Transcriptase Polymerase Chain Reaction / Q000379:methods; D020825:T-Box Domain Proteins; D006377:T-Lymphocytes, Helper-Inducer / Q000187:drug effects* / Q000378:metabolism; D018417:Th1 Cells / Q000187:drug effects / Q000378:metabolism; D018418:Th2 Cells / Q000187:drug effects* / Q000378:metabolism; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism*; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D000098815:T-bet Transcription Factor
D000906:Antibodies; D018106:CD28 Antigens; D017252:CD3 Complex; D016207:Cytokines; D004268:DNA-Binding Proteins; D050990:GATA3 Transcription Factor; C494748:Gata3 protein, mouse; D009294:Narcotics; D012333:RNA, Messenger; D020825:T-Box Domain Proteins; D000098815:T-bet Transcription Factor; D015534:Trans-Activators; D014157:Transcription Factors; D009020:Morphine; D004247:DNA