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* Infection Immunology and
Microbial Inflammation Research, Research Center Borstel, Borstel, Germany;
Molecular Inflammation Medicine, Christian Albrechts University, Kiel, Germany;
Institute of Medical Microbiology, Immunology and Hygiene, Technical University Munich, Munich, Germany;
¶ Department of Infectious Diseases and Immunology, St. Jude Children’s Research Hospital, Memphis, TN 38105; and
|| Institute of Clinical Microbiology, University Hospital Erlangen, Erlangen, Germany
Elevated IL-10 has been implicated in reactivation tuberculosis (TB). Since macrophages rather than T cells were reported to be the major source of IL-10 in TB, we analyzed the consequences of a macrophage-specific overexpression of IL-10 in transgenic mice (macIL-10-transgenic) after aerosol infection with Mycobacterium tuberculosis (Mtb). MacIL-10 transgenic mice were more susceptible to chronic Mtb infection than nontransgenic littermates, exhibiting higher bacterial loads in the lung after 12 wk of infection and dying significantly earlier than controls. The differentiation, recruitment, and activation of Th1 cells as well as the induction of IFN-
-dependent effector genes against Mtb were not affected by macrophage-derived IL-10. However, microarray analysis of pulmonary gene expression revealed patterns characteristic of alternative macrophage activation that were overrepresented in Mtb-infected macIL-10 transgenic mice. Importantly, arginase-1 gene expression and activity were strikingly enhanced in transgenic mice accompanied by a reduced production of reactive nitrogen intermediates. Moreover, IL-10-dependent arginase-1 induction diminished antimycobacterial effector mechanisms in macrophages. Taken together, macrophage-derived IL-10 triggers aspects of alternative macrophage activation and promotes Mtb recrudescence independent of overt effects on anti-TB T cell immunity.
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 This work is supported by a research grant ("Host defence against infections") from the Medical University of Lübeck (to C.H.), Bundesministerium für Bildung, Wissenschaft, Forschung und Technologie (Germany) Grants NIES05T22 (to S.E.), 01KI0784 (to S.E. and C.H.), and NGFN-2 FKZ 01GS0402 (to R.L.), the Deutsche Forschungsgemeinschaft La 1262/3-1 (to R.L.), and National Institutes of Health Grant AI062921 (to P.J.M.).
2 Current address: Center for Biological Safety, Robert Koch-Institute, Berlin, Germany.
3 Current address: GDD Common Mechanism Research, Bayer Schering Pharma AG, Berlin, Germany.
4 Address correspondence and reprint requests to Dr. Christoph Hölscher, Infection Immunology, Research Center Borstel, Parkallee 22, D-23845 Borstel, Germany. E-mail address: choelscher{at}fz-borstel.de
5 Abbreviations used in this paper: TB, tuberculosis; BMM
, bone marrow-derived macrophage; IL-4R
, IL-4 receptor ; MMP-12, matrix metalloproteinase-12; MMR, macrophage mannose receptor; Mtb, Mycobacterium tuberculosis; OADC, oleic acid-albumin-dextrose-catalase; RNI, reactive nitrogen intermediate; TfR, transferrin receptor.
6 The online version of this article contains supplemental material.
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