title: The influence of diesel exhaust particles on mononuclear phagocytic cell-derived cytokines: IL-10, TGF-beta and IL-1 beta.
abstract: Diesel exhaust particles (DEP) are known to modulate the production of cytokines associated with acute and chronic respiratory symptoms and allergic respiratory disease. Tolerance is an important mechanism through which the immune system can maintain nonresponsiveness to common environmental antigens. We examined the effect of DEP on IL-10 and TGF-beta, cytokines produced by macrophages and repressor (Tr-like) lymphocytes which influence tolerance. Human PBMCs (n = 22) were incubated with 1-100 ng/ml of DEP, and suboptimally primed with LPS. IL-10 gene expression was assessed by the S1 nuclease protection assay, and production of IL-10, TGF-beta, TNF-alpha, IL-1 beta and IL-4 stimulated CD23 was evaluated by ELISA after 24 and 48 h. The effect of the order of exposure to DEP and LPS was evaluated on IL-10 protein and mRNA in cells (1) preincubated with LPS followed by DEP, or (2) exposed first to DEP followed by LPS. IL-10 was further evaluated using benzo[a]pyrene and [alpha]naphthoflavone as a surrogate for the polyaromatic hydrocarbons (PAHs) adsorbed to DEP. Control cells were incubated with carbon black, without PAHs. In PBMCs exposed to DEP with LPS, or preincubated with LPS before DEP, IL-10 production and mRNA fall significantly. TGF-beta is similarly suppressed, IL-1 beta secretion is significantly stimulated, and IL-4 stimulated CD23 release rises in the atopic subjects. In contrast, when DEP is added prior to LPS, IL-10 production rises, and IL-1 beta falls to zero. These effects on IL-10 are reproduced with benzo[a]pyrene and reversed by the coaddition of [alpha]naphthoflavone, its known antagonist. The carbon black fraction has no effect on IL-10 production. The effect of DEP on IL-10 can be inhibitory or stimulatory, depending on the order of exposure to DEP and LPS. Pro-inflammatory cytokines and factors rise when IL-10 is inhibited, and are suppressed when IL-10 is stimulated. These results are duplicated with benzo[a]pyrene, suggesting that the PAH portion of the DEP is the active agent.
authors.affiliation: Department of Medicine, National Jewish Medical and Research Center, University of Colorado Health Sciences Center, Denver, Colorado 80206, USA. pachecok@njc.org
authors.forename: K A
authors.initials: KA
authors.lastname: Pacheco
authors.forename: M
authors.initials: M
authors.lastname: Tarkowski
authors.forename: C
authors.initials: C
authors.lastname: Sterritt
authors.forename: J
authors.initials: J
authors.lastname: Negri
authors.forename: L J
authors.initials: LJ
authors.lastname: Rosenwasser
authors.forename: L
authors.initials: L
authors.lastname: Borish
mesh_terms: D000328:Adult; D001564:Benzo(a)pyrene / Q000009:adverse effects; D001571:Benzoflavones / Q000494:pharmacology; D016535:Bronchial Hyperreactivity / Q000209:etiology / Q000276:immunology; D002244:Carbon / Q000494:pharmacology; D015870:Gene Expression / Q000187:drug effects; D006801:Humans; D006967:Hypersensitivity / Q000209:etiology; D066298:In Vitro Techniques; D007375:Interleukin-1 / Q000096:biosynthesis*; D016753:Interleukin-10 / Q000096:biosynthesis* / Q000235:genetics; D015847:Interleukin-4 / Q000494:pharmacology; D007963:Leukocytes, Mononuclear / Q000187:drug effects* / Q000276:immunology*; D008070:Lipopolysaccharides / Q000494:pharmacology; D008214:Lymphocytes / Q000187:drug effects / Q000276:immunology; D008264:Macrophages / Q000187:drug effects / Q000276:immunology; D008875:Middle Aged; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D017455:Receptors, IgE / Q000096:biosynthesis; D016212:Transforming Growth Factor beta / Q000096:biosynthesis*; D001335:Vehicle Emissions / Q000009:adverse effects*
chemical_list: D001571:Benzoflavones; D007375:Interleukin-1; D008070:Lipopolysaccharides; D012333:RNA, Messenger; D017455:Receptors, IgE; D016212:Transforming Growth Factor beta; D001335:Vehicle Emissions; D016753:Interleukin-10; D015847:Interleukin-4; D001564:Benzo(a)pyrene; C011512:alpha-naphthoflavone; D002244:Carbon