Mast cell (MC) heterogeneity has been well characterized in the rat where it has been shown that connective tissue MC, often represented by peritoneal MC (PMC), and the intestinal mucosal MC (IMMC) exhibit many differences in mediator content and responsiveness to secretagogues and anti-allergic drugs. Pretreatment (20 hr) of PMC with interferon (IFN)-alpha/beta or IFN-gamma, significantly reduced antigen-stimulated histamine release. By contrast, for IMMC, the same IFN treatment did not modify antigen-stimulated histamine secretion. Although IFN treatment differentially modulates histamine secretion from PMC and IMMC, pretreatment of both MC types with IFN-alpha/beta or IFN-gamma inhibited their tumour-necrosis factor-alpha (TNF-alpha)-dependent cytotoxicity. In 20 hr of culture, IMMC spontaneously released 98 pg/10 (6) MC of TNF-alpha, whereas PMC released about threefold more TNF-alpha, 282 pg/10 (6) MC. In addition, direct assessment of stored TNF-alpha established that IMMC store less TNF-alpha (68 pg/10 (6) MC) than PMC (404 pg/10 (6) MC). In summary, TNF-alpha content of PMC and IMMC was different, but IFN inhibited TNF-alpha-dependent cytotoxicity by both MC types. By contrast, treatment with IFN-alpha/beta or IFN-gamma inhibits antigen-induced histamine secretion by PMC, but does not modify antigen-induced histamine secretion by IMMC. Thus, IFN differentially regulate the secretion of histamine and TNF-alpha in PMC and IMMC.