Lung NF-kappaB activation and neutrophil recruitment require IL-1 and TNF receptor signaling during pneumococcal pneumonia.
Pulmonary inflammation is an essential component of the host defense against Streptococcus pneumoniae infection of the lungs. The early response cytokines, TNF-alpha and IL-1, are rapidly induced upon microbial exposure. Mice deficient in all TNF- and IL-1-dependent signaling receptors were used to determine the roles of these cytokines during pneumococcal pneumonia. The deficiency of signaling receptors for TNF and IL-1 decreased bacterial clearance. Neutrophil recruitment to alveolar air spaces was impaired by receptor deficiency, as was pulmonary expression of the neutrophil chemokines KC and MIP-2. Because NF-kappaB mediates the expression of both chemokines, we assessed NF-kappaB activation in the lungs. During pneumococcal pneumonia, NF-kappaB proteins translocate to the nucleus and activate gene expression; these functions were largely abrogated by the deficiency of receptors for TNF-alpha and IL-1. Thus, the combined deficiency of TNF and IL-1 signaling reduces innate immune responses to S. pneumoniae in the lungs, probably due to essential roles for these receptors in activating NF-kappaB.
Jones
Matthew R
MR
Physiology Program, Harvard School of Public Health, Boston, MA 02115, USA.
Simms
Benjamin T
BT
Lupa
Michal M
MM
Kogan
Mariya S
MS
Mizgerd
Joseph P
JP
D000818:Animals; D054426:Chemokine CXCL2; D018925:Chemokines / Q000096:biosynthesis / Q000276:immunology; D016207:Cytokines / Q000096:biosynthesis / Q000276:immunology; D004789:Enzyme Activation / Q000276:immunology; D015151:Immunoblotting; D007375:Interleukin-1 / Q000276:immunology; D008168:Lung / Q000276:immunology / Q000382:microbiology*; D051379:Mice; D008817:Mice, Mutant Strains; D016328:NF-kappa B / Q000276:immunology / Q000378:metabolism*; D020556:Neutrophil Infiltration / Q000276:immunology*; D011018:Pneumonia, Pneumococcal / Q000276:immunology* / Q000382:microbiology; D021381:Protein Transport / Q000276:immunology; D017472:Receptors, Interleukin-1 / Q000172:deficiency / Q000276:immunology*; D018124:Receptors, Tumor Necrosis Factor / Q000172:deficiency / Q000276:immunology*; D015398:Signal Transduction / Q000276:immunology; D014409:Tumor Necrosis Factor-alpha
D054426:Chemokine CXCL2; D018925:Chemokines; C404915:Cxcl2 protein, mouse; D016207:Cytokines; D007375:Interleukin-1; D016328:NF-kappa B; D017472:Receptors, Interleukin-1; D018124:Receptors, Tumor Necrosis Factor; D014409:Tumor Necrosis Factor-alpha