Reciprocity between IL-4 and opioid immune regulation: IL-4 primes human CD4+ T cells for opioid receptor driven MAP kinase signaling

Abstract

Abstract Opioid receptor (OR) signaling induces transcriptomic and functional changes in human T cell responses at both a molecular and cellular level, yet the signaling pathways initiated by OR engagement in human T cells are poorly characterized. ORs are G-protein coupled receptors with three subtypes: MuOR, KappaOR, and DeltaOR. Using the human lymphoma Jurkat T cell line and negatively selected human peripheral blood CD4 +T cells, the effects of opioid exposure on the activation kinetics of the MAP kinases ERK 1/2, JNK, and p38, scored as their level of phosphorylation, was followed by immunoblot. Opioid-driven phosphorylation of the MAPKs was dependent on IL-4 pretreatment of Jurkat cells, but not blood-derived CD4+ T cells. After Jurkat cells were primed with a 3-day exposure to IL-4, a series of opioid agonists selective for each OR subtype induced the phosphorylation of all three MAPKs (ERK, JNK, p38) within 2 min. Phosphorylation of the MAPKs was independent of OR subtype and opioid agonist. Notably, the kinetics were different than that observed in neurons. When primary human CD4 +T cells were treated with opioids, only p38 MAPK, not ERK or JNK, was activated with similar kinetics and OR subtype independence as that seen in Jurkat cells. This difference between primary cells and Jurkat cells suggests an additional level of regulation of opioid signaling in primary cells not found in Jurkat cells. The requirement for IL-4 pretreatment suggests that opioids may play a role in Th2 biology. Preliminary data indicate that morphine modestly increases the expression of IL-4 mRNA. Overall, these results reveal that p38 functions as a primary effector of opioid receptor signal transduction in human T cells. Supported by grants from NIH / NIDA (R01 DA 043253, )