title: Acute exposure to methamphetamine alters TLR9-mediated cytokine expression in human macrophage.
abstract: Recent studies show that methamphetamine (Meth) use leads to higher susceptibility to and progression of infections, which suggests impairment of the immune system. The first line of defense against infections is the innate immune system and the macrophage is a key player in preventing and fighting infections. So we profiled cytokines over time in Meth treated THP-1 cells, as a human macrophage model, at a relevant concentration using high throughput screening to find a signaling target. We showed that after a single exposure, the effect of Meth on macrophage cytokine production was rapid and time dependent and shifted the balance of expression of cytokines to pro-inflammatory. Our results were analogous to previous reports in that Meth up-regulates TNF-α and IL-8 after two hours of exposure. However, global screening led to the novel identification of CXCL16, CXCL1 and many other up-regulated cytokines. We also showed CCL7 as the most down-regulated chemokine due to Meth exposure, which led us to hypothesize that Meth dysregulates the MyD88-dependent Toll-like receptor 9 (TLR9) signaling pathway. In conclusion, altered cytokine expression in macrophages suggests it could lead to a suppressed innate immunity in people who use Meth.
authors.affiliation: Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, NE, USA.
authors.forename: Ariel
authors.initials: A
authors.lastname: Burns
authors.affiliation: Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, NE, USA. Electronic address: pciborowski@unmc.edu.
authors.forename: Pawel
authors.initials: P
authors.lastname: Ciborowski
mesh_terms: D002460:Cell Line; D000697:Central Nervous System Stimulants / Q000494:pharmacology*; D054410:Chemokine CCL7 / Q000235:genetics / Q000276:immunology; D054360:Chemokine CXCL1 / Q000235:genetics / Q000276:immunology; D000075743:Chemokine CXCL16; D019743:Chemokines, CXC / Q000235:genetics / Q000276:immunology; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D006801:Humans; D007113:Immunity, Innate; D016209:Interleukin-8 / Q000235:genetics / Q000276:immunology; D008264:Macrophages / Q000166:cytology / Q000187:drug effects* / Q000276:immunology; D008694:Methamphetamine / Q000494:pharmacology*; D053594:Myeloid Differentiation Factor 88 / Q000235:genetics / Q000276:immunology; D051116:Receptors, Scavenger / Q000235:genetics / Q000276:immunology; D015398:Signal Transduction / Q000187:drug effects* / Q000276:immunology; D051217:Toll-Like Receptor 9 / Q000235:genetics* / Q000276:immunology; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000276:immunology
chemical_list: C515450:CCL7 protein, human; C475829:CXCL1 protein, human; C423727:CXCL16 protein, human; D000697:Central Nervous System Stimulants; D054410:Chemokine CCL7; D054360:Chemokine CXCL1; D000075743:Chemokine CXCL16; D019743:Chemokines, CXC; D016209:Interleukin-8; C507779:MYD88 protein, human; D053594:Myeloid Differentiation Factor 88; D051116:Receptors, Scavenger; C495371:TLR9 protein, human; D051217:Toll-Like Receptor 9; D014409:Tumor Necrosis Factor-alpha; D008694:Methamphetamine
keywords: CCL7; Cytokine; Inflammation; Macrophage; Methamphetamine; Toll-like receptor signaling