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Infection and Immunity, December 2009, p. 5334-5346, Vol. 77, No. 12
0019-9567/09/$08.00+0     doi:10.1128/IAI.00883-09
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

Critical Role for Interleukin-1β (IL-1β) during Chlamydia muridarum Genital Infection and Bacterial Replication-Independent Secretion of IL-1β in Mouse Macrophages{triangledown}

Daniel Prantner,1 Toni Darville,1,2,{dagger} James D. Sikes,2 Charles W. Andrews Jr.,3 Helmut Brade,4 Roger G. Rank,1 and Uma M. Nagarajan1,2*

Department of Microbiology and Immunology, University of Arkansas for Medical Sciences, Little Rock, Arkansas 72205,1 Division of Pediatric Infectious Diseases, Arkansas Children's Hospital, Little Rock, Arkansas 72202,2 Department of Pathology, Rockdale Medical Center, Conyers, Georgia 30012,3 Research Center Borstel, Leibniz-Center for Medicine and Biosciences, Medical and Biochemical Microbiology, Parkallee 22, D-23845 Borstel, Germany4

Received 4 August 2009/ Returned for modification 24 August 2009/ Accepted 24 September 2009

Recent findings have implicated interleukin-1β (IL-1β) as an important mediator of the inflammatory response in the female genital tract during chlamydial infection. But how IL-1β is produced and its specific role in infection and pathology are unclear. Therefore, our goal was to determine the functional consequences and cellular sources of IL-1β expression during a chlamydial genital infection. In the present study, IL-1β–/– mice exhibited delayed chlamydial clearance and decreased frequency of hydrosalpinx compared to wild-type (WT) mice, implying an important role for IL-1β both in the clearance of infection and in the mediation of oviduct pathology. At the peak of IL-1β secretion in WT mice, the major producers of IL-1β in vivo are F4/80+ macrophages and GR-1+ neutrophils, but not CD45– epithelial cells. Although elicited mouse macrophages infected with Chlamydia muridarum in vitro secrete minimal IL-1β, in vitro prestimulation of macrophages by Toll-like receptor (TLR) ligands such as lipopolysaccharide (LPS) purified from Escherichia coli or C. trachomatis L2 prior to infection greatly enhanced secretion of IL-1β from these cells. By using LPS-primed macrophages as a model system, it was determined that IL-1β secretion was dependent on caspase-1, potassium efflux, and the activity of serine proteases. Significantly, chlamydia-induced IL-1β secretion in macrophages required bacterial viability but not growth. Our findings demonstrate that IL-1β secreted by macrophages and neutrophils has important effects in vivo during chlamydial infection. Additionally, prestimulation of macrophages by chlamydial TLR ligands may account for the elevated levels of pro-IL-1β mRNA observed in vivo in this cell type.

* Corresponding author. Mailing address: Division of Pediatric Infectious Diseases, Arkansas Children's Hospital Research Institute, 1120 Marshall Street, Room 2052, Little Rock, AR 72202. Phone: (501) 364-2479. Fax: (501) 364-2403. E-mail: nagarajanuma{at}uams.edu

{triangledown} Published ahead of print on 5 October 2009.

Editor: A. J. Bäumler

{dagger} Present address: Department of Pediatrics, Children's Hospital of Pittsburgh and University of Pittsburgh Medical Center, Pittsburgh, PA 15201.

Infection and Immunity, December 2009, p. 5334-5346, Vol. 77, No. 12
0019-9567/09/$08.00+0     doi:10.1128/IAI.00883-09
Copyright © 2009, American Society for Microbiology. All Rights Reserved.





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