TNF receptor 1 and 2 contribute in different ways to resistance to Legionella pneumophila-induced mortality in mice
Introduction
Tumor necrosis factor (TNF)-α is a pleiotropic cytokine which plays a critical role in controlling a vast array of immunological responses in the host defense. TNF-α is synthesized as a non-glycosylated, transmembrane protein, and then it undergoes cleavage by the specific metalloproteinase TNF-converting enzyme to form a soluble trimer. TNF-α binds to its two kinds of receptors (TNFR1 and TNFR2), present on virtually all cells throughout the body, and evokes a variety of reactions [1], [2], [3]. TNF-α contributes to innate immunity against intracellular proliferating bacilli such as Mycobacterium tuberculosis or Listeria monocytogenes [4], [5], [6], [7].
Legionella pneumophila has been recognized as a common pathogen of community-acquired pneumonia since 1976. The prevalence is reported to range from 1% to 30% in community-acquired pneumonia. This pathogen causes life-threatening pneumonia [8], [9]. Since L. pneumophila proliferates within host cells similar to M. tuberculosis or L. monocytogenes, TNF-α has been considered to play a critical role in the innate immunity against L. pneumophila. The secretion of TNF-α is an important autocrine defense mechanism of alveolar macrophages against L. pneumophila [10]. The neutrophils activated by the TNF-α contribute to the eradication of bacteria from infected lung tissues, thereby protecting the host [11]. In fact, the administration of TNF-α antibody has been reported to worsen L. pneumophila infection [12]. There is a clinical case report of L. pneumophila pneumonia occurring after infliximab, TNF antagonist, therapy for rheumatoid arthritis [13]. Such evidence clearly supports the importance of TNF-α in the immune response. However, the role of TNFR1 or TNFR2 on Legionella infection has not yet been clarified.
In this study, we investigated the role of TNFR in the host defense against L. pneumophila using TNFR1- or TNFR2-deficient mice. As a result, the important role of the TNF receptors in lung inflammation induced by L. pneumophila has been confirmed.
Section snippets
Bacteria
The Legionella spp. were obtained from the Gifu Type Culture Collection (GTC). The L. pneumophila Bloomington-2 strain (GTC 9137) and Philadelphia-1 strain (GTC 9134) were used. All strains were grown in buffered yeast extract (BYE) broth at 37 °C with shaking or on buffered charcoal yeast extract agar (BCYE; BYE with 0.2% activated charcoal and 1.5% Bacto agar) at 37 °C for 3 days. Both types of media were supplemented with 0.4-g/l of l-cysteine and 0.25-g/l ferric pyrophosphate, and the pH was
Results
The role of TNF-α on L. pneumophila infection was investigated using TNFR-deficient mice in vivo. After the intranasal instillation of 1 × 106 CFU/head of L. pneumophila, almost all the mice survived. All the mice died after 1 × 108 CFU/head of L. pneumophila inoculation. The TNFR1-KO mice and the TNFR2-KO mice demonstrated a high mortality rate in comparison to the wild-type mice after 1 × 107 CFU/head of L. pneumophila inoculation (Fig. 1).
The lung histology at day 1 after 1 × 107 CFU/head of L.
Discussion
TNF-α has been reported to play an important role in protective immunity against intracellularly proliferating bacteria such as L. pneumophila [4], [5], [6], [7]. The induction of TNF by L. pneumophila is involved in host defense, and the neutrophils activated by the TNF could clear the organism from the lung tissues, thereby protecting the animal [11]. Although the importance of TNF-α is evident, the role of its receptor remains uncleared issue. In the present study, the role of the TNF
Acknowledgments
We appreciate the assistance of Dr. Brian Quinn for editing the English usage.
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