title: Suppression of the NF-κB pathway by diesel exhaust particles impairs human antimycobacterial immunity.
abstract: Epidemiological studies suggest that chronic exposure to air pollution increases susceptibility to respiratory infections, including tuberculosis in humans. A possible link between particulate air pollutant exposure and antimycobacterial immunity has not been explored in human primary immune cells. We hypothesized that exposure to diesel exhaust particles (DEP), a major component of urban fine particulate matter, suppresses antimycobacterial human immune effector cell functions by modulating TLR-signaling pathways and NF-κB activation. We show that DEP and H37Ra, an avirulent laboratory strain of Mycobacterium tuberculosis, were both taken up by the same peripheral human blood monocytes. To examine the effects of DEP on M. tuberculosis-induced production of cytokines, PBMC were stimulated with DEP and M. tuberculosis or purified protein derivative. The production of M. tuberculosis and purified protein derivative-induced IFN-γ, TNF-α, IL-1β, and IL-6 was reduced in a DEP dose-dependent manner. In contrast, the production of anti-inflammatory IL-10 remained unchanged. Furthermore, DEP stimulation prior to M. tuberculosis infection altered the expression of TLR3, -4, -7, and -10 mRNAs and of a subset of M. tuberculosis-induced host genes including inhibition of expression of many NF-κB (e.g., CSF3, IFNG, IFNA, IFNB, IL1A, IL6, and NFKBIA) and IFN regulatory factor (e.g., IFNG, IFNA1, IFNB1, and CXCL10) pathway target genes. We propose that DEP downregulate M. tuberculosis-induced host gene expression via MyD88-dependent (IL6, IL1A, and PTGS2) as well as MyD88-independent (IFNA, IFNB) pathways. Prestimulation of PBMC with DEP suppressed the expression of proinflammatory mediators upon M. tuberculosis infection, inducing a hyporesponsive cellular state. Therefore, DEP alters crucial components of antimycobacterial host immune responses, providing a possible mechanism by which air pollutants alter antimicrobial immunity.
authors.affiliation: Department of Environmental and Occupational Health, University of Medicine and Dentistry of New Jersey-School of Public Health, Piscataway, NJ 08854, USA.
authors.forename: Srijata
authors.initials: S
authors.lastname: Sarkar
authors.forename: Youngmia
authors.initials: Y
authors.lastname: Song
authors.forename: Somak
authors.initials: S
authors.lastname: Sarkar
authors.forename: Howard M
authors.initials: HM
authors.lastname: Kipen
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Laumbach
authors.forename: Junfeng
authors.initials: J
authors.lastname: Zhang
authors.forename: Pamela A Ohman
authors.initials: PA
authors.lastname: Strickland
authors.forename: Carol R
authors.initials: CR
authors.lastname: Gardner
authors.forename: Stephan
authors.initials: S
authors.lastname: Schwander
mesh_terms: D000328:Adult; D017209:Apoptosis; D002470:Cell Survival; D005260:Female; D005786:Gene Expression Regulation; D006801:Humans; D008297:Male; D046529:Microscopy, Electron, Transmission; D008875:Middle Aged; D009000:Monocytes / Q000276:immunology* / Q000382:microbiology*; D009169:Mycobacterium tuberculosis; D016328:NF-kappa B / Q000276:immunology / Q000378:metabolism; D052638:Particulate Matter / Q000009:adverse effects* / Q000276:immunology; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000276:immunology; D014376:Tuberculosis / Q000276:immunology*; D001335:Vehicle Emissions / Q000633:toxicity*; D055815:Young Adult
chemical_list: D016328:NF-kappa B; D052638:Particulate Matter; D001335:Vehicle Emissions