CD40 ligation enhances IL-15 production by tubular epithelial cells.
Interleukin-15 (IL-15) is a potent T-cell growth factor and activator. Acute rejection of kidney allografts strongly correlated with elevated IL-15 mRNA in the graft. A role in the rejection process is also suggested for the interaction between CD40 ligand (CD154) expressed on membranes of activated T cells and its receptor (CD40). The effect of CD40 ligation on IL-15 production in human tubular epithelial cells (TEC) was investigated. TEC were co-cultured with a cell line genetically engineered to express CD154. CD154-expressing cells (CD40L cells) bind to TEC. Addition of the CD40L cells to the TEC culture resulted in elevated IL-15 levels. This enhanced production was not observed with control cells, when anti-CD154 antibody was added, and when direct contact between CD40L-cells and TEC was prevented with the use of a Trans-well system. CD40 activation resulted in a twofold increase of IL-15 mRNA transcripts as measured by reverse transcription-PCR and a concordant elevation in IL-15 protein production as measured by specific enzyme-linked immunosorbent assay. The intensity of activation by CD154 was linearly dependent on cell number, reaching plateau when the effector/target-ratio was 1:1. The increase of IL-15 levels was similar to that produced by stimulation with interferon-gamma (IFN-gamma). Combination of IFN-gamma and activation with CD154 resulted in an additive effect. To conclude, activated T cells may enhance IL-15 expression in two ways: by secreting IFN-gamma and by cell to cell contact using CD154. Each signal alone induces IL-15 in similar magnitudes, and both signals are additive. Because IL-15 is a major T-cell activator, this interaction may contribute to graft rejection.
Weiler
Michal
M
Department of Nephrology, Soroka University Medical Center, Ben-Gurion University of the Negev, Faculty of Health Sciences, Beer-Sheva, Israel.
Kachko
Leonid
L
Institute of Pathology, Soroka University Medical Center, Ben-Gurion University of the Negev, Faculty of Health Sciences, Beer-Sheva, Israel.
Chaimovitz
Cidio
C
Department of Nephrology, Soroka University Medical Center, Ben-Gurion University of the Negev, Faculty of Health Sciences, Beer-Sheva, Israel.
Kooten
Cees VAN
CV
Department of Nephrology, Leiden University Hospital, Leiden, The Netherlands.
Douvdevani
Amos
A
Department of Nephrology, Soroka University Medical Center, Ben-Gurion University of the Negev, Faculty of Health Sciences, Beer-Sheva, Israel.
D019013:CD40 Antigens / Q000378:metabolism*; D023201:CD40 Ligand / Q000378:metabolism / Q000494:pharmacology; D002478:Cells, Cultured; D004847:Epithelial Cells / Q000187:drug effects / Q000276:immunology; D006084:Graft Rejection / Q000209:etiology / Q000235:genetics / Q000276:immunology; D006801:Humans; D007371:Interferon-gamma / Q000494:pharmacology; D019409:Interleukin-15 / Q000096:biosynthesis* / Q000235:genetics; D016030:Kidney Transplantation / Q000009:adverse effects / Q000276:immunology; D007684:Kidney Tubules / Q000187:drug effects / Q000276:immunology*; D008024:Ligands; D008213:Lymphocyte Activation; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D011994:Recombinant Proteins; D013601:T-Lymphocytes / Q000276:immunology; D014184:Transplantation, Homologous
D019013:CD40 Antigens; D019409:Interleukin-15; D008024:Ligands; D012333:RNA, Messenger; D011994:Recombinant Proteins; D023201:CD40 Ligand; D007371:Interferon-gamma