Inflamed gingival tissues are enriched in macrophages (Mφs) and CD4- positive T cells; however, T helper-type cytokines such as interleukin (IL)- 2 and IL-4 are absent. Therefore, we investigated whether a relationship exists between IL-4 receptor (IL-4R) expression and Mφ persistence in the absence of exogenous IL-4. Gingival Mφs, when compared with monocyte(MN)/Mφs from peripheral blood mononuclear cells, expressed high levels of IL-4R mRNA. Furthermore, in vitro cultures of gingival Mφs remained viable whereas identically treated peripheral blood MN/Mφs rapidly lost viability. However, when gingival Mφs were incubated with recombinant IL-4 (rIL-4), the cell viability was dramatically reduced. When the frequency of apoptotic cells was assessed in rIL-4-treated gingival Mφ cultures, higher numbers of apoptotic cells were noted in rIL-4-treated versus control cultures. Furthermore, rIL-4-treated Mφs from inflamed gingiva showed DNA fragmentation as assessed by electrophoresis. These findings clearly show that addition of exogenous rIL-4 to gingival Mφ cultures leads to cell death by apoptosis. This finding would suggest that topical application of rIL-4 may inhibit the persistence of Mφs in adult periodontitis, which could then lead to decreased inflammation.