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J. Biol. Chem., Vol. 282, Issue 7, 4669-4680, February 16, 2007

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Synergistic and Differential Modulation of Immune Responses by Hsp60 and Lipopolysaccharide^*

Anke Osterloh, Supported by the Mildred-Scheel-Stiftung fuer Krebsforschung, Germany¹, Ulrich Kalinke, Siegfried Weiss^¶, Bernhard Fleischer, and Minka Breloer

From the Department of Immunology, Bernhard Nocht Institute for Tropical Medicine, 20359 Hamburg, Germany, the Department of Immunology, Paul Ehrlich Institute, 63225 Langen, Germany, and the ^¶Department of Molecular Immunology, HZI, Helmholtz Center for Infection Research, 38124 Braunschweig, Germany

Activation of professional antigen-presenting cells (APC) is a crucial step in the initiation of an efficient immune response. In this study we show that Hsp60 mediates immune stimulation by different mechanisms, dependent and independent of lipopolysaccharide (LPS). We have demonstrated earlier that both, Hsp60 and LPS, increase antigen-specific interferon (IFN) release in T cells. Here we show that in contrast to LPS Hsp60 induces IFN production in professional APC. Neutralization of IFN as well as the absence of functional IFN receptor on APC and T cells interfered with Hsp60-mediated IFN secretion in antigen-dependent T cell activation, strongly suggesting that IFN represents one factor contributing to Hsp60-specific immune stimulation. On the other hand, we show that Hsp60 bound to the cell surface of APC colocalizes with the LPS co-receptor CD14 and LPS binding sites. Hsp60 specifically binds bacterial LPS and both molecules synergistically enhanced IL-12p40 production in APC and IFN release in antigen-dependent T cell activation. This effect was Hsp60-specific and dependent on LPS-binding by Hsp60. Furthermore, we show that Hsp60 exclusively binds to macrophages and DC but not to T or B lymphocytes and that both, T cell stimulation by Hsp60 as well as Hsp60/LPS complexes, strictly depends on the presence of professional APC and is not mediated by B cells. Taken together, our data support an extension of the concept of Hsp60 as an endogenous danger signal: besides its function as a classical danger signal indicating unplanned tissue destruction to the innate immune system, in the incident of bacterial infection extracellular Hsp60 may bind LPS and facilitate microbe recognition by lowering the threshold of pathogen-associated molecular pattern (PAMP) detection and enhancing Toll-like receptor (TLR) signaling.

Received for publication, September 7, 2006 , and in revised form, December 1, 2006.

^* The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ To whom correspondence should be addressed. Tel.: 49-40-42818-243; Fax: 49-40-42818-400; E-mail: osterloh{at}bni.uni-hamburg.de.

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