AbstractTreatment of murine peritoneal macrophages for 30 min with lipopolysaccharide (LPS) resulted in a transient increase in c‐fos proto‐oncogene mRNA levels (Introna et al., 1986). After 2 h from the initial treatment, c‐fos mRNA could no longer be detected and its expression could not be restimulated either by LPS or by other signals including colony stimulating factor‐1 (CSF‐1) and phorbol myristate acetate (PMA), both of which are able to induce expression of the c‐fos gene in unstimulated macrophages. When LPS was removed after an initial 30 min incubation, responsiveness to a second exposure to LPS began to reappear after 3 h and was completely restored by 20 h. The same pattern of desensitization of c‐fos induction was observed when CSF‐1 stimulated macrophages were subsequently exposed to LPS. The loss of sensitivity to PMA following pretreatment with LPS was selective for c‐fos expression as LPS treated macrophages remained responsive to PMA with respect to the ability to stimulate secretion of H2O2. The mechanism of desensitization was localized, at least in part, at the level of transcription as demonstrated by analysis of c‐fos transcripts in nuclei isolated from macrophages pretreated and restimulated with LPS.