Morphine induces CD4+ T cell IL-4 expression through an adenylyl cyclase mechanism independent of the protein kinase A pathway.
Impaired host defense mechanisms after major operative procedures and trauma are recognized as important factors in the development of infectious complication. Trauma is associated with impaired cellular immunity and CD4+ T cell Th2 differentiation. We have previously implicated morphine treatment as a possible mechanism for Th2 differentiation after injury. In this investigation we first establish that morphine treatment in vivo results in Th2 differentiation and that this effect is mediated through a naltrexone-sensitive opioid receptor. We investigated the intracellular mechanism by which morphine controls CD4+ T cell differentiation and demonstrate that morphine treatment in vitro 1) increases anti CD3/CD28 Ab-induced CD4+ T cell IL-4 protein synthesis, IL-4 mRNA, and GATA-3 mRNA accumulation through a pertussis toxin-sensitive receptor; 2) results in a dose-dependent increase in anti-CD3/CD28 Ab-induced CD4+ T cell cytoplasmic cAMP concentration; and 3) increases the forskolin-stimulated cytoplasmic cAMP level through a pertussis toxin-sensitive receptor. We also demonstrate that chronic morphine treatment increases anti-CD3/CD28 Ab-induced IL-4 promoter activity and IL-4 immunoprotein expression through a p38 MAPK-dependent, but protein kinase A- and Erk1/Erk2-independent, mechanism.
Roy
Sabita
S
Department of Pharmacology, University of Minnesota, Minneapolis, MN 55455, USA. royxx002@umn.edu
Wang
Jinghua
J
Charboneau
Richard
R
Loh
Horace H
HH
Barke
Roderick A
RA
D000262:Adenylyl Cyclases / Q000378:metabolism*; D000818:Animals; D018106:CD28 Antigens / Q000378:metabolism; D017252:CD3 Complex / Q000378:metabolism; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology / Q000187:drug effects* / Q000201:enzymology / Q000276:immunology*; D002454:Cell Differentiation / Q000187:drug effects; D005576:Colforsin / Q000494:pharmacology; D000242:Cyclic AMP / Q000378:metabolism; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D006801:Humans; D066298:In Vitro Techniques; D015847:Interleukin-4 / Q000096:biosynthesis* / Q000235:genetics; D020935:MAP Kinase Signaling System / Q000187:drug effects; D051379:Mice; D008810:Mice, Inbred C57BL; D009020:Morphine / Q000008:administration & dosage / Q000494:pharmacology*; D037342:Pertussis Toxin / Q000494:pharmacology; D011401:Promoter Regions, Genetic / Q000187:drug effects; D018418:Th2 Cells / Q000166:cytology / Q000187:drug effects / Q000201:enzymology / Q000276:immunology; D014947:Wounds and Injuries / Q000188:drug therapy / Q000276:immunology
D018106:CD28 Antigens; D017252:CD3 Complex; D005576:Colforsin; D015847:Interleukin-4; D009020:Morphine; D000242:Cyclic AMP; D037342:Pertussis Toxin; D017868:Cyclic AMP-Dependent Protein Kinases; D000262:Adenylyl Cyclases