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Originally published online as doi:10.1189/jlb.0307147 on July 25, 2007

Published online before print July 25, 2007
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(Journal of Leukocyte Biology. 2007;82:1011-1018.)
© 2007 by Society for Leukocyte Biology

Mycobacterium paratuberculosis is recognized by Toll-like receptors and NOD2

Gerben Ferwerda*, Bart Jan Kullberg*, Dirk J. de Jong{dagger}, Stephen E. Girardin{ddagger}, Dennis M. L. Langenberg§, Reinout van Crevel*, Tom H. M. Ottenhoff§, Jos W. M. Van der Meer* and Mihai G. Netea*,1

* Department of Internal Medicine and Nijmegen University Center for Infectious Diseases and
{dagger} Department of Gastroenterology, Radboud University Nijmegen Medical Center, Nijmegen, The Netherlands;
{ddagger} Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada; and
§ Department of Immunohematology and Blood Transfusion, Leiden University Medical Centre, Leiden, The Netherlands

1 Correspondence: Department of Medicine (463), Radboud University Nijmegen Medical Center, Geert Grooteplein Zuid 8, 6525 GA Nijmegen, The Netherlands. E-mail: m.netea{at}aig.umcn.nl

Mycobacterium paratuberculosis has been suggested to be involved in the pathogenesis of Crohn's disease (CD). The importance of microorganisms in CD is supported by the association of CD with mutations in the intracellular pathogen recognition receptor (PRR) nucleotide-binding oligomerization domain 2 (NOD2). The aim of this study is to investigate the PRR involved in the recognition of M. paratuberculosis. Methods used include in vitro stimulation of transfected cell lines, murine macrophages, and human PBMC. M. paratuberculosis stimulated human TLR2 (hTLR2)-Chinese hamster ovary (CHO) cells predominantly and hTLR4-CHO cells modestly. Macrophages from TLR2 and TLR4 knockout mice produced less cytokines compared with controls after stimulation with M. paratuberculosis. TLR4 inhibition in human PBMC reduced cytokine production only after stimulation with live M. paratuberculosis. TLR-induced TNF-{alpha}, IL-1ß, and IL-10 production is mediated through MyD88, whereas Toll-IL-1R domain-containing adaptor inducing IFN-ß (TRIF) promoted the release of IL-1ß. hNOD2-human embryo kidney (HEK) cells, but not hNOD1-HEK cells, responded to stimulation with M. paratuberculosis. PBMC of individuals homozygous for the 3020insC NOD2 mutation showed a 70% defective cytokine response after stimulation with M. paratuberculosis. These results demonstrate that TLR2, TLR4, and NOD2 are involved in the recognition of M. paratuberculosis by the innate immune system.

Key Words: innate immunity • cytokines • monocytes • human • Crohn's disease




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