Accuri C6 Flow Cytometer System
Originally published online as doi:10.1189/jlb.1008587 on May 11, 2009

Published online before print May 11, 2009
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(Journal of Leukocyte Biology. 2009;86:303-312.)
© 2009 Society for Leukocyte Biology

Involvement of TLR2 and TLR4 in inflammatory immune responses induced by fine and coarse ambient air particulate matter

Joanna Shoenfelt*,1, Robert J. Mitkus{dagger},2, Rolf Zeisler§,3, Rabia O. Spatz§, Jan Powell{dagger},4, Matthew J. Fenton{ddagger},5, Katherine A. Squibb{dagger} and Andrei E. Medvedev*,6

* Departments of Microbiology and Immunology,
{dagger} Epidemiology and Preventive Medicine, and
{ddagger} Medicine, University of Maryland School of Medicine, Baltimore, Maryland, USA; and
§ Analytical Chemistry Division, National Institute of Standards and Technology, Gaithersburg, Maryland, USA

6. Correspondence: Department of Microbiology and Immunology, University of Maryland School of Medicine, 660 West Redwood St., Howard Hall Bldg., Rm. 324, Baltimore, MD 21201, USA. E-mail: amedvedev{at}som.umaryland.edu.

ABSTRACT

Induction of proinflammatory mediators by alveolar macrophages exposed to ambient air particulate matter has been suggested to be a key factor in the pathogenesis of inflammatory and allergic diseases in the lungs. However, receptors and mechanisms underlying these responses have not been fully elucidated. In this study, we examined whether TLR2, TLR4, and the key adaptor protein, MyD88, mediate the expression of proinflammatory cytokines and chemokines by mouse peritoneal macrophages exposed to fine and coarse PM. TLR2 deficiency blunted macrophage TNF-{alpha} and IL-6 expression in response to fine (PM2.5), while not affecting cytokine-inducing ability of coarse NIST Standard Reference Material (SRM 1648) particles. In contrast, TLR4–/– macrophages showed inhibited cytokine expression upon stimulation with NIST SRM 1648 but exhibited normal responses to PM2.5. Preincubation with polymyxin B markedly suppressed the capacity of NIST SRM 1648 to elicit TNF-{alpha} and IL-6, indicating endotoxin as a principal inducer of cytokine responses. Overexpression of TLR2 in TLR2/4-deficient human embryonic kidney 293 cells imparted PM2.5 sensitivity, as judged by IL-8 gene expression, whereas NIST SRM 1648, but not PM2.5 elicited IL-8 expression in 293/TLR4/MD-2 transfectants. Engagement of TLR4 by NIST SRM 1648 induced MyD88-independent expression of the chemokine RANTES, while TLR2-reactive NIST IRM PM2.5 failed to up-regulate this response. Consistent with the shared use of MyD88 by TLR2 and TLR4, cytokine responses of MyD88–/– macrophages to both types of air PM were significantly reduced. These data indicate differential utilization of TLR2 and TLR4 but shared use of MyD88 by fine and coarse air pollution particles.

Key Words: TLR • LPS • inflammation • signal transduction • cytokines




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