title: Δ⁹-Tetrahydrocannabinol-induced anti-inflammatory responses in adolescent mice switch to proinflammatory in adulthood.
abstract: Marijuana abuse is prominent among adolescents. Although Δ(9)-THC, one of its main components, has been demonstrated to modulate immunity in adults, little is known about its impact during adolescence on the immune system and the long-lasting effects in adulthood. We demonstrate that 10 days of Δ(9)-THC treatment induced a similar alteration of macrophage and splenocyte cytokines in adolescent and adult mice. Immediately at the end of chronic Δ(9)-THC, a decrease of proinflammatory cytokines IL- 1β and TNF-α and an increase of anti-inflammatory cytokine IL-10 production by macrophages were present as protein and mRNA in adolescent and adult mice. In splenocytes, Δ(9)-THC modulated Th1/Th2 cytokines skewing toward Th2: IFN-γ was reduced, and IL-4 and IL-10 increased. These effects were lost in adult animals, 47 days after the last administration. In contrast, in adult animals treated as adolescents, a perturbation of immune responses, although in an opposite direction, was present. In adults treated as adolescents, a proinflammatory macrophage phenotype was observed (IL-1β and TNF-α were elevated; IL-10 decreased), and the production of Th cytokines was blunted. IgM titers were also reduced. Corticosterone concentrations indicate a long-lasting dysregulation of HPA in adolescent mice. We measured blood concentrations of Δ(9)-THC and its metabolites, showing that Δ(9)-THC plasma levels in our mice are in the order of those achieved in human heavy smokers. Our data demonstrate that Δ(9)-THC in adolescent mice triggers immune dysfunctions that last long after the end of abuse, switching the murine immune system to proinflammatory status in adulthood.
authors.affiliation: Dipartimento di Scienze Farmacologiche e Biomolecolari, Università degli Studi di Milano, Milano, Italy;
authors.forename: Sarah
authors.initials: S
authors.lastname: Moretti
authors.affiliation: Dipartimento di Scienze Farmacologiche e Biomolecolari, Università degli Studi di Milano, Milano, Italy;
authors.forename: Mara
authors.initials: M
authors.lastname: Castelli
authors.affiliation: Dipartimento di Scienze Farmacologiche e Biomolecolari, Università degli Studi di Milano, Milano, Italy;
authors.forename: Silvia
authors.initials: S
authors.lastname: Franchi
authors.affiliation: Department of Pharmacy and Biotechnology, Alma Mater Studiorum, University of Bologna, Italy; and.
authors.forename: Maria Augusta
authors.initials: MA
authors.lastname: Raggi
authors.affiliation: Department of Pharmacy and Biotechnology, Alma Mater Studiorum, University of Bologna, Italy; and.
authors.forename: Laura
authors.initials: L
authors.lastname: Mercolini
authors.affiliation: Department of Pharmacy and Biotechnology, Alma Mater Studiorum, University of Bologna, Italy; and.
authors.forename: Michele
authors.initials: M
authors.lastname: Protti
authors.affiliation: Addiction Treatment Centre, Local Health Service, Cossato, Biella, Italy.
authors.forename: Lorenzo
authors.initials: L
authors.lastname: Somaini
authors.affiliation: Dipartimento di Scienze Farmacologiche e Biomolecolari, Università degli Studi di Milano, Milano, Italy;
authors.forename: Alberto E
authors.initials: AE
authors.lastname: Panerai
authors.affiliation: Dipartimento di Scienze Farmacologiche e Biomolecolari, Università degli Studi di Milano, Milano, Italy; paola.sacerdote@unimi.it.
authors.forename: Paola
authors.initials: P
authors.lastname: Sacerdote
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D016207:Cytokines / Q000096:biosynthesis; D013759:Dronabinol / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D006433:Hemocyanins / Q000276:immunology / Q000494:pharmacology; D007075:Immunoglobulin M / Q000276:immunology; D008264:Macrophages / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D008297:Male; D051379:Mice; D010587:Phagocytosis / Q000187:drug effects / Q000276:immunology; D013154:Spleen / Q000166:cytology / Q000276:immunology / Q000378:metabolism
chemical_list: D000893:Anti-Inflammatory Agents; D016207:Cytokines; D007075:Immunoglobulin M; D013759:Dronabinol; D006433:Hemocyanins; C032808:keyhole-limpet hemocyanin
keywords: cytokines; immune response; liquid chromatography-mass spectrometry; marijuana