Major involvement of CD40 in the regulation of chemokine secretion from human peritoneal mesothelial cells

Background. CD40 is a member of the tumor necrosis factor (TNF) family of receptors, whose ligand, CD154, is expressed by activated mononuclear cells. CD40 activation is a major immune regulatory pathway and is important for the regulation of chemokine and cytokine secretion. This study investigates the effect of CD40 ligation on the secretion of chemokines from human peritoneal mesothelial cells (HPMC). Methods. We activated CD40 in HPMC along with combinations of TNF-α, interleukin-1 (IL-1), and interferon gamma (IFN-γ), and evaluated the mRNA levels and protein secretion of regulated upon activation, normal T-cell expressed and secreted (RANTES), monocyte chemoattractant protein-1 (MCP-1), and IL-8. Results. CD40 ligation had a small stimulatory effect on the secretion of all three chemokines, while TNF-α, IL-1 and IFN-γ induced their secretion in a dose-dependent manner. The combination of CD40 ligation with either IL-1 or TNF-α increased chemokine secretion additively. IFN-γ and CD40 ligation acted in synergy to induce the secretion of the mononuclear recruiting chemokines RANTES and MCP-1 (up to ∼36-fold and ∼ threefold, respectively), for which the combination of all three cytokines with CD40 ligation was extremely potent. In contrast, the secretion of the neutrophil chemoattractant IL-8, induced by CD40 ligation or by the combination of IL-1 and TNF-α, was reduced in the presence of IFN-γ. Conclusion. In light of our data, it is reasonable to suggest that in the mononuclear phase of peritonitis, IFN-γ and CD154, expressed by activated mononuclear cells, diminish IL-8 secretion from HPMC and thus inhibit neutrophil recruitment. At the same time, the two act in synergy to induce the secretion of RANTES and MCP-1 from HPMC. Hence, by regulating chemokine secretion, CD40 may be involved in peritonitis and in the development of late phase mononuclear predominance.