We have examined the expression of inducible inflammatory genes in murine macrophages from different tissues and at different stages of inflammatory activity. Although i.v. administration of IFN-gamma (10,000 U/mouse) strongly induced expression of IP-10 mRNA in the adherent cell population of the spleen, thioglycollate-elicited peritoneal macrophages were essentially unresponsive at the same dose. In contrast, D3 mRNA was expressed in both cell populations. This differential sensitivity of IP-10 mRNA expression was not restricted to stimulation by IFN-gamma as it was also seen when LPS (25 micrograms/mouse) was administered i.v. Expression of JE and KC mRNA, which encode cytokines related to IP-10, were also differentially expressed in elicited peritoneal macrophages from mice injected with LPS. Differential sensitivity was at least partially related to the state of macrophage activation because IP-10 mRNA was highly inducible in resident but not thioglycollate-elicited peritoneal macrophages. The eliciting agent was also an important determinant because proteose-peptone-elicited peritoneal macrophages were nearly as sensitive as splenic macrophages with respect to expression of IP-10 mRNA. IFN-gamma treatment induced IP-10 and D3 mRNA rapidly and transiently with the same time course in the spleen. IP-10 mRNA was not induced by IFN-gamma in TG-elicited macrophages regardless of the time after treatment. This differential expression of IP-10 was a consequence of different concentration requirements for IFN-gamma in the two cell types; thioglycollate-elicited macrophages required five- to 10-fold more IFN-gamma than did resident cells to achieve comparable IP-10 mRNA levels whether the agent was provided in vitro or in vivo. Thus variable sensitivity for induction of IP-10 mRNA was a characteristic of the macrophage itself and was not mediated by other cellular or molecular elements present in the inflammatory peritoneal cavity. The reduced sensitivity to IFN-gamma or LPS for expression of IP-10, JE, and KC mRNA as compared with TNF-alpha or D3 mRNA suggests that this distinct pattern of regulation may be restricted to members of these two related cytokine gene families that exhibit cell-type specific chemoattractant activity.