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PMID: 15793291 Published · ppublish English Comparative Study Journal Article Research Support, Non-U.S. Gov't

Contribution of transmembrane tumor necrosis factor to host defense against Mycobacterium bovis bacillus Calmette-guerin and Mycobacterium tuberculosis infections.

The American journal of pathology ·Vol. 166 ·No. 4 ·2005-04-00 ·Pages 1109-20

Olleros ML, Guler R, Vesin D, Parapanov R, Marchal G, Martinez-Soria E, Corazza N, Pache JC, Mueller C, Garcia I

Abstract

To study the specific role of transmembrane tumor necrosis factor (TmTNF) in host defense mechanisms against bacillus Calmette-Guerin (BCG) and Mycobacterium tuberculosis infections, we compared the immune responses of TNF/lymphotoxin (LT)-alpha(-/-) mice expressing a noncleavable transgenic TmTNF (TmTNF tg) to those of TNF/LT-alpha(-/-) and wild-type mice. Susceptibility of TNF/LT-alpha(-/-) mice to BCG infection was associated with impaired induction of systemic RANTES but not of monocyte chemoattractant protein 1 (MCP-1), the development of excessive local and systemic Th1-type immune responses, and a substantially reduced inducible nitric oxide synthase (iNOS) activity. Resistance of TmTNF tg mice to BCG infection was associated with efficient activation of iNOS in granulomas and with the regulated release of local and systemic chemokines and Th1-type cytokines. However, M. tuberculosis infection of TmTNF tg mice resulted in longer survival and enhanced resistance compared to TNF/LT-alpha(-/-) mice but higher sensitivity than wild-type mice. TmTNF tg mice exhibited reduced pulmonary iNOS expression and showed an exacerbated cellular infiltration in the lungs despite a modest bacillary content. Our data thus indicate a role for TmTNF in host defense against mycobacteria by contributing to induction and regulation of Th1-type cytokine and chemokine expression leading to development of bactericidal granulomas expressing iNOS, which critically determines susceptibility versus resistance of the host to mycobacterial infections.

MeSH Terms
Animals Bronchoalveolar Lavage Fluid/cytology,immunology Chemokine CCL2/metabolism Chemokine CCL5/metabolism Cytokines/metabolism Flow Cytometry Granuloma/immunology Immunohistochemistry In Situ Hybridization Lung/cytology,immunology,pathology Lymphotoxin-alpha/genetics,immunology Mice Mice, Transgenic Mycobacterium bovis/immunology Nitric Oxide Synthase/immunology,metabolism Nitric Oxide Synthase Type II Spleen/cytology,immunology Tuberculosis/immunology,pathology,veterinary Tumor Necrosis Factor-alpha/genetics,immunology
Chemicals
Ccl2 protein, mouse Chemokine CCL2 Chemokine CCL5 Cytokines Lymphotoxin-alpha Tumor Necrosis Factor-alpha Nitric Oxide Synthase Nitric Oxide Synthase Type II Nos2 protein, mouse
Authors & Affiliations
10 authors, click to expand affiliations / ORCID
Olleros Maria L
Department of Pathology and Immunology, University of Geneva, Geneva, Switzerland.
Guler Reto
Vesin Dominique
Parapanov Roumen
Marchal Gilles
Martinez-Soria Eduardo
Corazza Nadia
Pache Jean-Claude
Mueller Christoph
Garcia Irene
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Article Info
Journal
The American journal of pathology
Abbr.
Am J Pathol
ISSN
0002-9440
DOI
10.1016/S0002-9440(10)62331-0
Published
2005-04-00
Pages
1109-20
Language
English
Region
United States
NLM ID
0370502
PMCID
PMC1602380
Subset
IM
External Links
PubMed source DOI: 10.1016/S0002-9440(10)62331-0 PMC Full Text View journal details
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