Morphine Withdrawal Stress Modulates Lipopolysaccharide-induced Interleukin 12 p40 (IL-12p40) Expression by Activating Extracellular Signal-regulated Kinase 1/2, Which Is Further Potentiated by Glucocorticoids
Year: 2011
Type: article
Abstract: Withdrawal stress is a common occurrence in opioid users, yet very few studies have examined the effects of morphine withdrawal (MW) on immune functioning or the role of glucocorticoids in MW-induced immunomodulation. This study investigated for the first time the role of glucocorticoids in MW modulation of LPS-induced IL-12p40, a key cytokine playing a pivotal role in immunoprotection. Using WT and μ-opioid receptor knock-out mice, we show that MW in vivo significantly attenuated LPS-induced IL-12p40 mRNA and protein expression. The role of glucocorticoids in MW modulation of IL-12p40 was investigated using a murine macrophage cell line, CRL2019, in an in vitro MW model. Interestingly, MW alone in the absence of glucocorticoids resulted in a significant reduction in IL-12p40 promoter activity and mRNA and protein expression. EMSA revealed a concurrent decrease in consensus binding to transcription factors NFκB, Activator Protein-1, and CCAAT/enhancer-binding protein and Western blot analysis demonstrated a significant activation of LPS-induced ERK1/2 phosphorylation. Interestingly, although glucocorticoid treatment alone also modulated these transcription factors and ERK1/2 activation, the addition of glucocorticoids to MW samples resulted in a greater than additive reduction in the transcription factors and significant hyperactivation of LPS-induced ERK1/2 phosphorylation. ERK inhibitors reversed MW and MW plus corticosterone inhibition of LPS-induced IL-12p40. The potentiating effects of glucocorticoids were non-genomic because nuclear translocation of glucocorticoid receptor was not significantly different between MW and corticosterone treatment. This study demonstrates for the first time that MW and glucocorticoids independently modulate IL-12p40 production through a mechanism involving ERK1/2 hyperactivation and that glucocorticoids can significantly augment MW-induced inhibition of IL-12p40.
Source: Journal of Biological Chemistry
Language: English
Subfield: Cellular and Molecular Neuroscience
Field: Neuroscience
Domain: Life Sciences
Open Access status: hybrid
Estimated APC paid: $3,430
Funder: National Institute on Drug Abuse
Awards: Opioid Drug abuse in the context of opportunistic infection increases susceptibil, Basic Research Center on Molecular and Cell Biology of Drug Abuse, G4573561219, Morphine, HIV proteins, wound healing and Infection, Role of microRNAs in opioid drug abuse induced persistent Inflammation and HIV di, Training in PharmacoNeuroImmune Substance Abuse Research, Role of Microbial dysbiosis and altered metabolomics in the context of Opioid abuse and ART in HIV disease progression, Opioid Abuse, opportunistic infection and NeuroAIDS, Role of Mu Opioid Receptor in Immune Function
OpenAlex ID: W2075669278