title: Polychlorinated Biphenyls (PCB 101, 153, and 180) Impair Murine Macrophage Responsiveness to Lipopolysaccharide: Involvement of NF-κB Pathway.
abstract: Non-dioxin-like (NDL) polychlorinated biphenyls (PCBs) are persistent organic pollutants, associated with a range of adverse health effects, including interference with the immune system. In this study, we investigate the capability of NDL-PCBs 101, 153, and 180, 3 of the 6 NDL-PCBs defined as indicators, to impair the immune response in lipopolysaccharide (LPS)-activated J774A.1 and primary murine macrophages. Our results clearly demonstrate that the exposure of J774A.1 and primary macrophages to NDL-PCB 153 or 180 or all NDL-PCBs mixtures causes a significant reduction in LPS-induced cytokine/chemokine synthesis, such as tumor necrosis factor-α and interleukin-6, together with monocyte chemoattractant protein-1, involved in cell recruitment. Moreover, PCBs were found to suppress LPS-stimulated NO production, and to reduce cyclooxygenase-2 and inducible nitric oxide synthase expression in J774A.1 and primary macrophages. At mechanistic level, PCBs significantly counteract the LPS-driven toll-like receptor (TLR) 4 and CD14 upregulation, therefore inhibiting downstream nuclear factor-κB (NF-κB) activation in J774A.1. Furthermore, PCBs determine a significant loss of macrophage endocytic capacity, a prerequisite for efficient antigen presentation. Taken together, these data indicate that NDL-PCBs reduce macrophage responsiveness, particularly when they are combined at concentrations per se inactive, impairing the capability to orchestrate a proper immune response to an infectious stimulus, disrupting TLR4/NF-κB pathway.
authors.affiliation: *Department of Pharmacy;
authors.forename: Anna
authors.initials: A
authors.lastname: Santoro
authors.affiliation: Department of Pathology and Animal Health; and.
authors.forename: Maria C
authors.initials: MC
authors.lastname: Ferrante
authors.affiliation: *Department of Pharmacy;
authors.forename: Francesca
authors.initials: F
authors.lastname: Di Guida
authors.affiliation: *Department of Pharmacy;
authors.forename: Claudio
authors.initials: C
authors.lastname: Pirozzi
authors.affiliation: *Department of Pharmacy;
authors.forename: Adriano
authors.initials: A
authors.lastname: Lama
authors.affiliation: *Department of Pharmacy;
authors.forename: Raffaele
authors.initials: R
authors.lastname: Simeoli
authors.affiliation: Department of Pathology and Animal Health; and.
authors.forename: Maria T
authors.initials: MT
authors.lastname: Clausi
authors.affiliation: Department of Pathology and Animal Health; and.
authors.forename: Anna
authors.initials: A
authors.lastname: Monnolo
authors.affiliation: Department of Biology, University of Naples Federico II, 80131 Naples, Italy.
authors.forename: Maria Pina
authors.initials: MP
authors.lastname: Mollica
authors.affiliation: *Department of Pharmacy;
authors.forename: Giuseppina
authors.initials: G
authors.lastname: Mattace Raso
authors.affiliation: *Department of Pharmacy; meli@unina.it.
authors.forename: Rosaria
authors.initials: R
authors.lastname: Meli
mesh_terms: D000818:Animals; D002470:Cell Survival / Q000187:drug effects; D018925:Chemokines / Q000096:biosynthesis; D051546:Cyclooxygenase 2 / Q000378:metabolism; D016207:Cytokines / Q000096:biosynthesis; D004705:Endocytosis / Q000187:drug effects; D004785:Environmental Pollutants / Q000633:toxicity*; D018950:Lipopolysaccharide Receptors / Q000096:biosynthesis / Q000187:drug effects; D008070:Lipopolysaccharides / Q000494:pharmacology*; D008262:Macrophage Activation / Q000187:drug effects; D008264:Macrophages / Q000187:drug effects*; D008297:Male; D016328:NF-kappa B / Q000187:drug effects*; D009569:Nitric Oxide / Q000378:metabolism; D011078:Polychlorinated Biphenyls / Q000633:toxicity*; D061251:Primary Cell Culture; D051381:Rats; D017208:Rats, Wistar; D015398:Signal Transduction / Q000187:drug effects; D051197:Toll-Like Receptor 4 / Q000096:biosynthesis / Q000187:drug effects
chemical_list: D018925:Chemokines; D016207:Cytokines; D004785:Environmental Pollutants; D018950:Lipopolysaccharide Receptors; D008070:Lipopolysaccharides; D016328:NF-kappa B; C495347:Tlr4 protein, rat; D051197:Toll-Like Receptor 4; D009569:Nitric Oxide; D011078:Polychlorinated Biphenyls; D051546:Cyclooxygenase 2
keywords: NF-κB, toll-like receptor 4; endocytosis; immune suppression; lipopolysaccharide; non-dioxin-like polychlorinated biphenyls