Chronic morphine treatment promotes specific Th2 cytokine production by murine T cells in vitro via a Fas/Fas ligand-dependent mechanism.
Improper homeostasis of Th1 and Th2 cell differentiation can promote pathological immune responses such as autoimmunity and asthma. A number of factors govern the development of these cells including TCR ligation, costimulation, death effector expression, and activation-induced cell death (AICD). Although chronic morphine administration has been shown to selectively promote Th2 development in unpurified T cell populations, the direct effects of chronic morphine on Th cell skewing and cytokine production by CD4(+) T cells have not been elucidated. We previously showed that morphine enhances Fas death receptor expression in a T cell hybridoma and human PBL. In addition, we have demonstrated a role for Fas, Fas ligand (FasL), and TRAIL in promoting Th2 development via killing of Th1 cells. Therefore, we analyzed whether the ability of morphine to affect Th2 cytokine production was mediated by regulation of Fas, FasL, and TRAIL expression and AICD directly in purified Th cells. We found that morphine significantly promoted IL-4 and IL-13 production but did not alter IL-5 or IFN-gamma. Furthermore, morphine enhanced the mRNA expression of Fas, FasL and TRAIL and promoted Fas-mediated AICD of CD4(+) T cells. Additionally, blockade of Fas/FasL interaction by anti-FasL inhibited the morphine-induced production of IL-4 and IL-13 and AICD of CD4(+) T cells. These results suggest that morphine preferentially enhances Th2 cell differentiation via killing of Th1 cells in a Fas/FasL-dependent manner.
Greeneltch
Kristy M
KM
Department of Immunology, Jerome H. Holland Laboratory for the Biomedical Sciences, American Red Cross, Rockville, MD 20855, USA.
Kelly-Welch
Ann E
AE
Shi
Yufang
Y
Keegan
Achsah D
AD
D000818:Animals; D000906:Antibodies; D017209:Apoptosis / Q000187:drug effects; D051017:Apoptosis Regulatory Proteins / Q000096:biosynthesis / Q000235:genetics; D002454:Cell Differentiation / Q000187:drug effects; D016207:Cytokines / Q000096:biosynthesis*; D053222:Fas Ligand Protein; D005260:Female; D018793:Interleukin-13 / Q000096:biosynthesis; D015847:Interleukin-4 / Q000096:biosynthesis; D008562:Membrane Glycoproteins / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D009020:Morphine / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D009271:Naltrexone / Q000494:pharmacology; D009294:Narcotics / Q000494:pharmacology*; D012333:RNA, Messenger / Q000378:metabolism; D018124:Receptors, Tumor Necrosis Factor / Q000235:genetics / Q000502:physiology*; D053221:TNF-Related Apoptosis-Inducing Ligand; D018418:Th2 Cells / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis / Q000235:genetics; D048069:Tumor Necrosis Factors / Q000235:genetics / Q000276:immunology / Q000502:physiology*; D019014:fas Receptor
D000906:Antibodies; D051017:Apoptosis Regulatory Proteins; D016207:Cytokines; C505661:FASLG protein, human; D053222:Fas Ligand Protein; C491899:Fas protein, mouse; C505658:Fasl protein, mouse; D018793:Interleukin-13; D008562:Membrane Glycoproteins; D009294:Narcotics; D012333:RNA, Messenger; D018124:Receptors, Tumor Necrosis Factor; D053221:TNF-Related Apoptosis-Inducing Ligand; C505653:TNFSF10 protein, human; C505654:Tnfsf10 protein, mouse; D014409:Tumor Necrosis Factor-alpha; D048069:Tumor Necrosis Factors; D019014:fas Receptor; D015847:Interleukin-4; D009271:Naltrexone; D009020:Morphine