CVI Accepts, published online ahead of print on 4 November 2009

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Clin. Vaccine Immunol. doi:10.1128/CVI.00336-09
Copyright (c) 2009, American Society for Microbiology and/or the Listed Authors/Institutions. All Rights Reserved.

Immunomodulatory properties of Yersinia pestis lipopolysaccharides on human macrophages

Motohiro Matsuura^*, Hideyuki Takahashi, Haruo Watanabe, Shinji Saito, and Kazuyoshi Kawahara

Department of Infection and Immunity, School of Medicine, Jichi Medical University, Tochigi 329-0498, Japan; Department of Bacteriology, National Institute of Infectious Disease, Tokyo 162-8640, Japan; Graduate School of Comprehensive Human Sciences, University of Tsukuba, Ibaraki 305-8575, Japan; and College of Engineering, Kanto Gakuin University, Yokohama 236-8501, Japan

^* To whom correspondence should be addressed. Email: mmatsuur{at}jichi.ac.jp.

In the current study, we investigated the activity of lipopolysaccharide (LPS) purified from Yersinia pestis grown at either 27°C or 37°C (termed LPS-27 and LPS-37, respectively). LPS-27 containing hexa-acylated lipid A, similar to LPS present in usual gram-negative bacteria, stimulated an inflammatory response in human U937 cells through Toll-like receptor 4 (TLR4). LPS-37 that did not contain hexa-acylated lipid A exhibited strong antagonistic activity to the TLR4 mediated inflammatory response. The phagocytic activity in the cells was not affected by LPS-37. To estimate the activity of LPS in its bacterial binding form, formalin-killed bacteria (FKB) were prepared from Y. pestis grown at the two temperatures (termed FKB-27 and FKB-37, respectively). FKB-27 demonstrated a strong stimulation of the inflammatory response. This activity was suppressed in the presence of an anti-TLR4 antibody, but not anti-TLR2 antibody. In addition, this activity was almost completely suppressed by LPS-37, indicating that the activity of FKB-27 is predominantly derived from the LPS-27 bacterial binding form. In contrast, FKB-37 showed no antagonistic activity. The results arising from the current study indicate that Y. pestis causes infection in humans without stimulating the TLR4-based defense system via bacterial binding of LPS-37 even when bacterial free LPS-37 to suppress the defense system is not released. This is in contrast to bacteria that possess agonistic LPS types that are easily recognized by the defense system via the bacterial binding forms.