Tumor necrosis factor mediates lung antibacterial host defense in murine Klebsiella pneumonia

Abstract

Tumor necrosis factor (TNF) is a proinflammatory cytokine which has recently been shown to have beneficial effects in the setting of acquired host immunity. However, the role of TNF in innate immune responses, as in the setting of bacterial pneumonia, has been incompletely characterized. To determine the role of TNF in gram-negative bacterial pneumonia, CBA/J mice were challenged with 10 2 CFU of Klebsiella pneumoniae intratracheally, resulting in the time-dependent expression of TNF MRNA and protein within the lung. Passive immunization of animals with a soluble TNF receptor-immunoglobulin (Ig) construct (sTNFR:Fc) intraperitoneally 2 h prior to K. pneumoniae inoculation resulted in a significant reduction in bronchoalveolar lavage neutrophils, but not macrophages, at 48 h, as compared with animals receiving control IgG1. Furthermore, treatment with sTNFR:Fc resulted in 19.6-and 13.5-fold increases in K. pneumoniae CFU in lung homogenates and plasma, respectively, as compared with animals receiving control IgG1. Finally, treatment of Klebsiellainfected mice with sTNFR:Fc markedly decreased both short-and long-term survival of these animals. In conclusion, our studies indicate that endogenous TNF is a critical component of antibacterial host defense in murine Klebsiella pneumonia.

Endogenous Tumor Necrosis Factor (TNF) α Mediates Neutrophil Accumulation at the Mid‐Phase of a Murine Model of Pseudomonas aeruginosa Pneumonia

“…Similar compartmentalized TNF responses in the lungs have been shown in animals intratracheally challenged with Escherichia coli LPS (16), live Legionella pneumophila (2) or live Klebsiella pneumoniae (10). However, the literature describing animal models with pneumonia have not evaluated the presence of bacteremia (2,10). The mechanism of absence of TNF a activity in this study remains unknown.…”

“…Although marked bacteremia occurrred in the mid-phase of fatal pneumonia, TNF activity was not detected in the plasma during the course of fatal infection. Similar compartmentalized TNF responses in the lungs have been shown in animals intratracheally challenged with Escherichia coli LPS (16), live Legionella pneumophila (2) or live Klebsiella pneumoniae (10). However, the literature describing animal models with pneumonia have not evaluated the presence of bacteremia (2,10).…”

The effect of Pseudomonas exotoxin A on cytokine production in whole blood exposed to Pseudomonas aeruginosa

“…Pneumonia is associated with local production of cytokines and chemokines. Locally produced TNF prevents outgrowth of bacteria in lungs, thereby playing a protective role in experimental pneumonia with Streptococcus pneumoniae [12,33], Klebsiella pneumoniae [11] and Legionella pneumophila [34]. Like TNF, IL-6 plays an important role in host defense in pneumococcal pneumonia [12], as do chemokines in K. pneumoniae pneumonia [25] and in P. aeruginosa infection [35].…”

Elevated CO2selectively inhibits interleukin‐6 and tumor necrosis factor expression and decreases phagocytosis in the macrophage

“…To explore the possibility that hypercapnia interferes with host defense, we investigated the effects of elevated P CO2 on macrophage innate immune responses. Our data show that in macrophages stimulated with lipopolysaccharide (LPS) and other Toll-like receptor (TLR) ligands, normoxic hypercapnia inhibited expression of the nuclear factor (NF)-B-dependent cytokines, tumor necrosis factor (TNF), and interleukin (IL)-6, which play well-documented roles in antimicrobial host defense (11)(12)(13)(14)(15)(16)(17)(18)(19)(20)(21)(22). Inhibition of TNF and IL-6 expression was selective, as hypercapnia did not affect LPS induction of IL-10 or interferon (IFN)-␤.…”