The effects of bacterial lipopolysaccharide (LPS) on macrophage gene expression are mediated in part by its ability to induce activation of transcription factor NF-kappa B. We compared the ability of LPS-treated macrophages from Lpsn (LPS-responsive) C3H/HeN and Lpsd (LPS-hyporesponsive) C3H/HeJ mice to mobilize NF-kappa B by electrophoretic mobility shift assays with oligonucleotide probes containing a unique NF-kappa B sequence from the promoter of inducible nitric oxide synthase (iNOS). In response to ng/ml concentrations of LPS, this probe bound proteins that appeared rapidly in the nuclei of thioglycollate-elicited macrophages and bone marrow-derived macrophage cell lines from both Lpsn and Lpsd mice. Only in macrophages from Lpsn mice, however, was LPS able to induce iNOS or tumor necrosis factor alpha. NF-kappa B-containing DNA-protein complexes from Lpsd macrophages were formed in lesser amounts than from Lpsn macrophages but shared the same composition, insofar as they displayed the same electrophoretic mobilities and content of heterodimers of p50/RelA (p65) and p50/c-rel. Two conclusions emerge from these findings: (1) NF-kappa B activity alone is not sufficient for induction of certain LPS-responsive genes and (2) An LPS-response pathway involving activation of NF-kappa B is preserved in Lpsd mice. The inability of cells from Lpsd mice to induce gene expression in response to LPS thus cannot be attributed to inability to activate NF-kappa B.