Chronic Morphine Treatment Promotes Specific Th2 Cytokine Production by Murine T Cells In Vitro via a Fas/Fas Ligand-Dependent Mechanism

Abstract

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-γ. 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.

Morphine, but Not Ketamine, Decreases the Ratio of Th1/Th2 in CD4-positive Cells Through T-bet and GATA3

“…Further, morphine was found to increase Th2 cell derived cytokines in chronic treatment models [19]. We did not find that morphine can increase Th2 cell subset perhaps for the short duration of morphine's treatment in our study.…”

Immunization with autologous T cells enhances in vivo anti-tumor immune responses accompanied by up-regulation of GADD45β

“…There are many factors involved in the AICD. Fas and FasL are very important proteins in the AICD process [36,37]. Fas is a molecule expressed on activated T cells and serves as an activation marker for T cells.…”

Cholestasis induced nephrotoxicity: The role of endogenous opioids

“…Chronic exposure to exogenous opioid receptor agonists also increases vulnerability to apoptosis in the liver as well as neurons and certain tumor cell lines (Dawson et al 1997;Hatsukari et al 2003;Hatsukari et al 2007;Payabvash et al 2006). Morphine through the sustained activation of opioid receptors, can promote abnormal programmed cell death by enhancing the expression of pro-apoptotic FasL, Fas, and Bad proteins, and damping the expression of antiapoptotic Bcl-2 oncoprotein (Boronat et al 2001;Greeneltch et al 2005;Jaume et al 2004). Weber et al (2008) examined the effect of exogenous opioid treatment (chronic morphine) and reported an increase in kidney weight and glomerular volume in C57/BL6 WT mice.…”