CD40 FUNCTION IN NONHEMATOPOIETIC CELLS - NUCLEAR FACTOR KAPPA-B MOBILIZATION AND INDUCTION OF IL-6 PRODUCTION

CD40 is a member of the TNF receptor family that was first characteriz ed as an important T-B cell interaction molecule. This receptor is als o expressed on many other cell types, including normal basal epitheliu m, carcinomas, and transformed cell lines, The functions of CD40 in no n-B cells are largely unknown. Our studies demonstrate that CD40 media tes nuclear factor kappa B (NF-kappa B) mobilization and IL-6 producti on in nonhematopoietic cells, Stimulation of the transformed fibroblas t cell line SV80 with CD40 ligand (CD40L) or anti-CD40 Ab resulted in the production of IL-6; this could be increased by IFN-gamma pretreatm ent, which is known to up-regulate CD40 expression. Studies with trans fectants overexpressing CD40 demonstrated that activation of CD40 alon e is sufficient to induce IL-6 production. The transcription factor NF -kappa B appears to play a central role in CD40-mediated activation of the IL-6 gene; NF-kappa B mobilization directly preceded CD40-mediate d IL-6 production, and suppression of NF-kappa B mobilization with the metabolic inhibitor D609 also suppressed the IL-6 response. A strikin g similarity to the requirements for TNF-induced IL-6 production, whic h is mediated by the p55TNF receptor in SV80 cells, was observed. In v iew of the intracellular homologies between CD40 and the p55TNF recept or, it should be considered that the two receptors share common compon ents in their signaling pathways that lead to IL-6 production.