Prantner Daniel, Darville Toni, Sikes James D, Andrews Charles W, Brade Helmut, Rank Roger G, Nagarajan Uma M
Department of Microbiology and Immunology, University of Arkansas for Medical Sciences, Little Rock, Arkansas 72205, USA.
Infect Immun. 2009 Dec;77(12):5334-46. doi: 10.1128/IAI.00883-09. Epub 2009 Oct 5.
Recent findings have implicated interleukin-1beta (IL-1beta) as an important mediator of the inflammatory response in the female genital tract during chlamydial infection. But how IL-1beta 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-1beta expression during a chlamydial genital infection. In the present study, IL-1beta(-/-) mice exhibited delayed chlamydial clearance and decreased frequency of hydrosalpinx compared to wild-type (WT) mice, implying an important role for IL-1beta both in the clearance of infection and in the mediation of oviduct pathology. At the peak of IL-1beta secretion in WT mice, the major producers of IL-1beta 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-1beta, 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-1beta from these cells. By using LPS-primed macrophages as a model system, it was determined that IL-1beta secretion was dependent on caspase-1, potassium efflux, and the activity of serine proteases. Significantly, chlamydia-induced IL-1beta secretion in macrophages required bacterial viability but not growth. Our findings demonstrate that IL-1beta 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-1beta mRNA observed in vivo in this cell type.
最近的研究结果表明，白细胞介素-1β（IL-1β）是衣原体感染期间女性生殖道炎症反应的重要介质。但IL-1β如何产生及其在感染和病理过程中的具体作用尚不清楚。因此，我们的目标是确定衣原体生殖道感染期间IL-1β表达的功能后果和细胞来源。在本研究中，与野生型（WT）小鼠相比，IL-1β基因敲除（-/-）小鼠衣原体清除延迟，输卵管积水频率降低，这意味着IL-1β在感染清除和输卵管病理介导中起重要作用。在WT小鼠IL-1β分泌高峰期，体内IL-1β的主要产生者是F4/80（+）巨噬细胞和GR-1（+）中性粒细胞，而不是CD45（-）上皮细胞。虽然体外感染鼠衣原体的诱导型小鼠巨噬细胞分泌的IL-1β极少，但在感染前用Toll样受体（TLR）配体如从大肠杆菌或沙眼衣原体L2中纯化的脂多糖（LPS）对巨噬细胞进行体外预刺激，可大大增强这些细胞IL-1β的分泌。以LPS预处理的巨噬细胞作为模型系统，确定IL-1β分泌依赖于半胱天冬酶-1、钾外流和丝氨酸蛋白酶的活性。值得注意的是，衣原体诱导的巨噬细胞IL-1β分泌需要细菌存活但不需要生长。我们的研究结果表明，巨噬细胞和中性粒细胞分泌的IL-1β在衣原体感染期间在体内具有重要作用。此外，衣原体TLR配体对巨噬细胞的预刺激可能解释了在体内该细胞类型中观察到的前体IL-1β mRNA水平升高的原因。
