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Infection and Immunity, July 2009, p. 2683-2690, Vol. 77, No. 7
0019-9567/09/$08.00+0 doi:10.1128/IAI.00248-09
Copyright © 2009, American Society for Microbiology. All Rights Reserved.
Chlamydial Heat Shock Protein 60 Induces Acute Pulmonary Inflammation in Mice via the Toll-Like Receptor 4- and MyD88-Dependent Pathway
Yonca Bulut,1,
Kenichi Shimada,2,
Michelle H. Wong,2
Shuang Chen,2
Pearl Gray,2
Randa Alsabeh,3
Terence M. Doherty,2
Timothy R. Crother,2 and
Moshe Arditi2*
Pediatric Critical Care, Mattel Children's Hospital at UCLA, Los Angeles, California,1 Pediatrics Infectious Diseases, Cedars-Sinai Medical Center, University of California, Los Angeles, California 90048,2 Department of Pathology and Laboratory Medicine, Cedars-Sinai Medical Center, University of California, Los Angeles, California 900483
Received 4 March 2009/ Returned for modification 8 April 2009/ Accepted 20 April 2009
Heat shock protein 60 derived from Chlamydia pneumoniae (cHSP60) activates Toll-like receptor 4 (TLR4) signaling through the MyD88 pathway in vitro, but it is not known how cHSP60 contributes to C. pneumoniae-induced lung inflammation. We treated wild-type (WT), TLR2–/–, TLR4–/–, or MyD88–/– mice intratracheally (i.t.) with recombinant cHSP60 (50 µg), UV-killed C. pneumoniae (UVCP; 5 x 106 inclusion-forming units/mouse), lipopolysaccharide (2 µg), or phosphate-buffered saline (PBS) and sacrificed mice 24 h later. Bronchoalveolar lavage (BAL) was obtained to measure cell counts and cytokine levels, lungs were analyzed for histopathology, and lung homogenate chemokine concentrations were determined. Bone marrow-derived dendritic cells (BMDDCs) were generated and stimulated with live C. pneumoniae (multiplicity of infection [MOI], 5), UVCP (MOI, 5), or cHSP60 for 24 h, and the expression of costimulatory molecules (CD80 and CD86) was measured by fluorescence-activated cell sorting. cHSP60 induced acute lung inflammation with the same intensity as that of UVCP-induced inflammation in WT mice but not in TLR4–/– or MyD88–/– mice. cHSP60- and UVCP-induced lung inflammation was associated with increased numbers of cells in BAL, increased neutrophil recruitment, and elevated BAL interleukin-6 (IL-6) levels. Both cHSP60 and UVCP induced IL-6 release and CD80 and CD86 expression in WT cells but not in MyD88–/– BMDDCs. cHSP60 stimulated DC activation in a TLR4- and MyD88-dependent manner with an intensity similar to that induced by UVCP. These data suggest that cHSP60 promotes lung inflammation and DC activation via TLR4 and MyD88 and therefore may play a significant role in the pathogenesis of C. pneumoniae-induced chronic inflammatory lung diseases.
* Corresponding author. Mailing address: Cedars-Sinai Medical Center, Division of Pediatrics Infectious Diseases and Immunology, 8700 Beverly Boulevard, Room 4220, Los Angeles, CA 90048. Phone: (310) 423-4064. Fax: (310) 423-8284. E-mail: moshe.arditi{at}cshs.org
Published ahead of print on 27 April 2009.
These authors contributed equally to this work.
Infection and Immunity, July 2009, p. 2683-2690, Vol. 77, No. 7
0019-9567/09/$08.00+0 doi:10.1128/IAI.00248-09
Copyright © 2009, American Society for Microbiology. All Rights Reserved.
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