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J. Biol. Chem., Vol. 279, Issue 1, 245-250, January 2, 2004
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Helicobacter pylori Heat Shock Protein 60 Mediates Interleukin-6 Production by Macrophages via a Toll-like Receptor (TLR)-2-, TLR-4-, and Myeloid Differentiation Factor 88-independent Mechanism*
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From the
Unité de Pathogénie Bactérienne des Muqueuses (UPBM), **Unité de Bactériologie Moléculaire et Médicale, and Unité Défense Innée et Inflammation, INSERM E336, Institut Pasteur, Paris Cedex15, France and the Department of Microbiology, National University of Ireland, IRL Galway, Ireland
Helicobacter pylori has been reported to induce interleukin-6 (IL-6) production in monocytes/macrophages and in chronically inflamed gastric tissues. The mechanism by which H. pylori induces IL-6 production in macrophages, however, has not been investigated. To identify the H. pylori factor responsible for this activity, we fractionated soluble proteins from H. pylori strain 26695 by ion exchange and size exclusion chromatography and screened the fractions for IL-6-inducing activity on RAW 264.7 macrophages. A single protein was purified and identified by mass spectrometry as H. pylori heat shock protein 60 (HSP60). Consistent with the observed IL-6-inducing activity of H. pylori HSP60, soluble protein extracts of H. pylori 26695 and SS1 strains that were depleted of this protein by affinity chromatography had dramatically reduced IL-6-inducing activities. The immunopurified HSP60 stimulated IL-6 production in macrophages. When stimulated with H. pylori HSP60 or intact bacteria, peritoneal macrophages from mice deficient in Toll-like receptor (TLR)-2, TLR-4, TLR-2/TLR-4, and myeloid differentiation factor 88 produced the same amount of IL-6 than macrophages from wild-type mice, demonstrating the independence of H. pylori HSP60 responses from these signaling molecules. H. pylori HSP60-induced IL-6 mRNA expression, and NF-
B activation in RAW 264.7 cells was abrogated in the presence of MG-132, a proteasome inhibitor. In contrast, inhibitors of protein kinase A or C, mitogen-activated protein kinase kinase, and phosphoinositide 3-kinase had no effect on IL-6 mRNA levels. This study demonstrates the induction of innate immune responses by H. pylori HSP60, thereby implicating this highly conserved protein in the pathophysiology of chronic gastritis.
Received for publication, July 21, 2003 , and in revised form, October 15, 2003.
* This work was funded by the Institut Pasteur (PTR 94) (to C. W., M. C., and R. L. F.) and ARC (project number 4428) (to R. L. F.). 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.
Supported by a Bourse Roux postdoctoral fellowship from the Institut Pasteur.
¶ Present address: Laboratoire de Microbiologie, Inra de Clermont-Ferrand-Thiex, F-63122 Saint-Genes-Champanelle, France.
|| Present address: EMI 0212, Faculte Necker Enfants-malades, 75743 Paris, France.
¶¶ Supported by the Health Research Board (Ireland).
|||| To whom correspondence should be addressed: UPBM, Institut Pasteur, 28 rue du Docteur Roux, 75724 Paris, France. Tel.: 33-1-40613324; Fax: 33-1-40613640; E-mail: rferrero{at}pasteur.fr.
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