Abstract
BackgroundTranscription factors have distinct functions in regulating immune responses. During Escherichia coli pneumonia, deficiency of NF-κB p50 increases gene expression and neutrophil recruitment, suggesting that p50 normally limits these innate immune responses. p50-deficient mice were used to determine how p50 regulates responses to a simpler, non-viable bacterial stimulus in the lungs, E. coli lipopolysaccharide (LPS).ResultsIn contrast to previous results with living E. coli, neutrophil accumulation elicited by E. coli LPS in the lungs was decreased by p50 deficiency, to approximately 30% of wild type levels. Heat-killed E. coli induced neutrophil accumulation which was not decreased by p50 deficiency, demonstrating that bacterial growth and metabolism were not responsible for the different responses to bacteria and LPS. p50 deficiency increased the LPS-induced expression of κB-regulated genes essential to neutrophil recruitment, including KC, MIP-2, ICAM-1, and TNF-α suggesting that p50 normally limited this gene expression and that decreased neutrophil recruitment did not result from insufficient expression of these genes. Neutrophils were responsive to the chemokine KC in the peripheral blood of p50-deficient mice with or without LPS-induced pulmonary inflammation. Interleukin-6 (IL-6), previously demonstrated to decrease LPS-induced neutrophil recruitment in the lungs, was increased by p50 deficiency, but LPS-induced neutrophil recruitment was decreased by p50 deficiency even in IL-6 deficient mice.Conclusionp50 makes essential contributions to neutrophil accumulation elicited by LPS in the lungs. This p50-dependent pathway for neutrophil accumulation can be overcome by bacterial products other than LPS and does not require IL-6.
Highlights
Transcription factors have distinct functions in regulating immune responses
Effect of p50 deficiency on neutrophil recruitment elicited by heat-killed E. coli The observation that p50 deficiency decreased neutrophil recruitment elicited by E. coli LPS in the lungs was surprising in light of previous studies indicating no such effect of p50 deficiency on neutrophil recruitment elicited by E. coli in the lungs [25]
Neutrophils were observed in the alveolar air spaces after the instillation of heat-killed E. coli, and there were no significant differences between genotypes (Figure 2)
Summary
Transcription factors have distinct functions in regulating immune responses. During Escherichia coli pneumonia, deficiency of NF-κB p50 increases gene expression and neutrophil recruitment, suggesting that p50 normally limits these innate immune responses. p50deficient mice were used to determine how p50 regulates responses to a simpler, non-viable bacterial stimulus in the lungs, E. coli lipopolysaccharide (LPS). During Escherichia coli pneumonia, deficiency of NF-κB p50 increases gene expression and neutrophil recruitment, suggesting that p50 normally limits these innate immune responses. The innate immune response to bacteria in the lungs requires the recruitment and activation of neutrophils, mediated by the coordinated expression of diverse genes (see [1] for review). Neutrophils recognize at least 2 chemokines (KC and macrophage inflammatory protein-2, MIP-2) that are synthesized de novo in response to gram-negative bacteria or LPS in the lungs, and each is independently essential to maximal neutrophil recruitment [2,3,4]. ICAM1 is constitutively expressed, but LPS and gram-negative bacteria in the lungs result in increased expression [5,6] and ICAM-1 is required for maximal neutrophil emigration [7,8]. NF-κB proteins may mediate the LPSinduced expression of genes controlling neutrophil emigration in the lungs
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