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PMID: 18524936 Published · ppublish English Journal Article Research Support, N.I.H., Extramural

A role for tumour necrosis factor-alpha, complement C5 and interleukin-6 in the initiation and development of the mycobacterial cord factor trehalose 6,6'-dimycolate induced granulomatous response.

Microbiology (Reading, England) ·Vol. 154 ·No. Pt 6 ·2008-06-00 ·Pages 1813-1824

Welsh KJ, Abbott AN, Hwang SA, Indrigo J, Armitige LY, Blackburn MR, Hunter RL, Actor JK

Abstract

Trehalose 6,6'-dimycolate (TDM) is a glycolipid component of the mycobacterial cell wall that causes immune responses in mice similar to Mycobacterium tuberculosis (MTB) infection, including granuloma formation with production of proinflammatory cytokines. The precise roles of tumour necrosis factor (TNF)-alpha, complement C5 and interleukin (IL)-6 in the molecular events that lead to the initiation and maintenance of the granulomatous response to TDM have not been fully elucidated. Macrophage proinflammatory responses from wild-type and complement-deficient mice after infection with MTB were assessed, and compared to responses from organisms in which surface TDM had been removed. Removal of TDM abolished proinflammatory responses, markedly so in the complement-deficient macrophages. Mice deficient in TNF-alpha, C5a and IL-6, along with wild-type C57BL/6 controls, were intravenously injected with TDM in a water-in-oil emulsion, and analysed for histological response and cytokine production in lungs. Wild-type C57BL/6 mice formed granulomas with increased production of IL-1beta, IL-6, TNF-alpha, macrophage inflammatory protein-1alpha (MIP-1alpha), IL-12p40, interferon-gamma (IFN-gamma), and IL-10 protein and mRNA. TNF-alpha-deficient mice failed to produce a histological response to TDM, with no increases in cytokine production following TDM administration. While C5a-deficient mice exhibited inflammation, they did not form structured granulomas and initially had decreased production of proinflammatory mediators. IL-6-deficient mice initiated granuloma formation, but failed to maintain the granulomas through day 7 and demonstrated decreased early production of proinflammatory mediators in comparison to wild-type mice. These data suggest that TNF-alpha is critical for initiation of the granulomatous response, C5a is necessary for formation of cohesive granulomas, and IL-6 plays a key role in the granuloma maintenance response to mycobacterial TDM.

MeSH Terms
Adjuvants, Immunologic/pharmacology Animals Complement C5a/deficiency,genetics,immunology Cord Factors/pharmacology Cytokines/deficiency,genetics,immunology Female Gene Expression Profiling Granuloma, Respiratory Tract/immunology Interleukin-6/deficiency,genetics,immunology Lung/pathology Macrophages/drug effects,immunology Mice Mice, Inbred C57BL Mycobacterium tuberculosis/immunology RNA, Messenger/analysis Tuberculosis/immunology,pathology Tumor Necrosis Factor-alpha/deficiency,genetics,immunology
Chemicals
Adjuvants, Immunologic Cord Factors Cytokines Interleukin-6 RNA, Messenger Tumor Necrosis Factor-alpha Complement C5a
Authors & Affiliations
8 authors, click to expand affiliations / ORCID
Welsh Kerry J
Medical School, University of Texas-Houston, Houston, TX 77030, USA.
Abbott April N
Graduate School of Biomedical Sciences, Program in Molecular Pathology, University of Texas-Houston Health Science Center, Houston, TX, USA.
Hwang Shen-An
Graduate School of Biomedical Sciences, Program in Molecular Pathology, University of Texas-Houston Health Science Center, Houston, TX, USA.
Indrigo Jessica
Corporate and Foundation Relations, Washington University School of Medicine, St Louis, MO 63105, USA.
Armitige Lisa Y
Department of Internal Medicine-Infectious Diseases, Medical School, University of Texas-Houston, Houston, TX, USA. | Graduate School of Biomedical Sciences, Program in Molecular Pathology, University of Texas-Houston Health Science Center, Houston, TX, USA. | Medical School, University of Texas-Houston, Houston, TX 77030, USA.
Blackburn Michael R
Department of Biochemistry and Molecular Biology, Medical School, University of Texas-Houston, Houston, TX, USA. | Graduate School of Biomedical Sciences, Program in Molecular Pathology, University of Texas-Houston Health Science Center, Houston, TX, USA. | Medical School, University of Texas-Houston, Houston, TX 77030, USA.
Hunter Robert L
Department of Pathology, Medical School, University of Texas-Houston, Houston, TX, USA. | Graduate School of Biomedical Sciences, Program in Molecular Pathology, University of Texas-Houston Health Science Center, Houston, TX, USA. | Medical School, University of Texas-Houston, Houston, TX 77030, USA.
Actor Jeffrey K
Department of Pathology, Medical School, University of Texas-Houston, Houston, TX, USA. | Graduate School of Biomedical Sciences, Program in Molecular Pathology, University of Texas-Houston Health Science Center, Houston, TX, USA. | Medical School, University of Texas-Houston, Houston, TX 77030, USA.
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Article Info
Journal
Microbiology (Reading, England)
Abbr.
Microbiology (Reading)
ISSN
1350-0872
DOI
10.1099/mic.0.2008/016923-0
Published
2008-06-00
Pages
1813-1824
Language
English
Region
England
NLM ID
9430468
PMCID
PMC2556040
Subset
IM
Grants
NHLBI NIH HHS · R01HL068537 · United States
NIAID NIH HHS · 1R21AI058247-1 · United States
NHLBI NIH HHS · R21 HL080313-02 · United States
NHLBI NIH HHS · R21 HL080313 · United States
NHLBI NIH HHS · R01 HL068537 · United States
External Links
PubMed source DOI: 10.1099/mic.0.2008/016923-0 PMC Full Text View journal details
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