- Abstract . Limited data are available concerning the interaction between lymphocytes and human peritoneal mesothelial cells (HPMC) during peritonitis. CD40 is a member of the tumor necrosis factor (TNF) family of receptors whose ligand (CD154) is mainly expressed on the membrane of activated CD4-positive lymphocytes. CD154-CD40 cross-linking is a central event in antigen presentation, B-cell activation by T cells, and regulation of cytokine secretion from various types of cells. The goal of this study was to demonstrate in vitro the presence of CD40 on HPMC and to test its functionality in inducing interleukin-15 (IL-15) and RANTES. We assayed the levels of CD40 by reverse transcription-PCR and flow cytometry and IL-15 and RANTES by enzyme-linked immunosorbent assay. Genetically modified L cells that express elevated levels of CD154 (CD40L cells) were used to stimulate CD40. HPMC express CD40 mRNA and protein. After stimulation with interferon-γ (IFNγ, 5U/ml) or TNFα (1 ng/ml), there was a small increase in CD40 mRNA and protein levels; when both cytokines were applied, the increase in CD40 levels was more than threefold. CD40 ligation induced IL-15 production by HPMC and was additive to IFNγ stimulation. CD40 ligation was strongly synergistic with IFNγ in induction of RANTES (20-fold as compared with unstimulated HPMC), whereas neither ligation nor IFNγ alone could induce RANTES. Pretreatment of HPMC with TNFα and IFNγ increased the response to CD40 ligation in magnitudes that correlated with the elevation of CD40 levels induced by the pretreatment. To conclude, the presence of a functional CD40 on HPMC whose ligation induced IL-15 and RANTES production was detected. It is possible that this receptor acts as a major mediator of T-cell—regulated immune and inflammatory response during peritonitis.