Rationale: Neutrophil recruitment to the lung after lipopolysaccharide (endotoxin) inhalation is primarily dependent on Tlr4 signaling, since it is virtually absent in mice deficient in Tlr4. However, among strains wild type for Tlr4, the magnitude of neutrophil recruitment to the lung after LPS inhalation is variable, suggesting the involvement of genes other than Tlr4. Objective: To identify genes associated with the inflammatory response to inhaled endotoxin, we evaluated the transcriptional response in the lungs of twelve inbred strains of mice, eight which are wild type for the Tlr4 receptor and four which lack a functional Tlr4 receptor. Methods: Using the Promoter Integration in Microarray Analysis (PRIMA) algorithm, we scanned our gene list for transcription factor binding sites significantly over-represented among Tlr4 wild type strains with high neutrophil influx in the lung after endotoxin inhalation. Results: This analysis identified the interferon-stimulated response element (ISRE) as the most over-represented transcription factor (present in 24% of the promoters) associated with the neutrophil influx to the lower respiratory tract. To test the validity of this observation, we evaluated interferon gamma (IFN-) deficient mice, and found that the presence of IFN- is essential for robust neutrophil recruitment to the lower respiratory tract and modulation of key regulatory cytokines and chemokines following endotoxin inhalation. Conclusions: Using a genomic approach, we identified the ISRE as a transcriptional element associated with the neutrophil response to inhaled endotoxin, and demonstrated for the first time that IFN- plays a critical role in endotoxin-induced neutrophil recruitment to the lower airways.