title: Synergistic effect of IL-1alpha, IFN-gamma, and TNF-alpha on RANTES production by human renal tubular epithelial cells in vitro.
abstract: Interstitial rejection of renal allografts is associated with infiltrating mononuclear cells. Mechanisms leading to this mononuclear cell influx are still not fully resolved. The chemokine RANTES (Regulated upon Activation, Normal T cell Expressed and Secreted) is chemotactic for monocytes and T cells. In renal allograft biopsies of patients undergoing rejection, RANTES is found in infiltrating monocytes and T cells, as well as in the tubular epithelium. This study analyzes the production of RANTES in vitro by proximal tubular epithelial cells (PTEC) after stimulation with the inflammatory cytokines interleukin-1alpha, (IL-1alpha), interferon-gamma (IFN-gamma), and tumor necrosis factor-alpha (TNF-alpha). Unstimulated PTEC or PTEC stimulated with the cytokines IL-1alpha, IFN-gamma, and TNF-alpha alone did not produce detectable amounts of RANTES. However, a combination of IFN-gamma and either IL-1alpha or TNF-alpha resulted in strong induction of RANTES production up to 2046 +/- 817 pg/ml or 2595 +/- 525 pg/ml per 1 x 10(5) PTEC, respectively. After stimulation with IL-1alpha and TNF-alpha, RANTES production was less prominent than the combination of IFN-gamma with either IL-1alpha or TNF-alpha, and only detectable in 5 of 7 PTEC lines tested. The production of RANTES was both dose- and time-dependent and was inhibited by cycloheximide, indicating that de novo protein synthesis is required. Because the production of RANTES by PTEC is more pronounced in the presence of T cell-derived IFN-gamma (in combination with either IL-1alpha or TNF-alpha), it was hypothesized that RANTES produced by PTEC presumably plays a prominent role in the amplification phase of the immune response rather than in the initiation phase.
authors.affiliation: Department of Nephrology, Leiden University Hospital, The Netherlands.
authors.forename: J G
authors.initials: JG
authors.lastname: Deckers
authors.forename: F J
authors.initials: FJ
authors.lastname: Van Der Woude
authors.forename: S W
authors.initials: SW
authors.lastname: Van Der Kooij
authors.forename: M R
authors.initials: MR
authors.lastname: Daha
mesh_terms: D000906:Antibodies; D001667:Binding, Competitive; D002460:Cell Line / Q000187:drug effects; D018946:Chemokine CCL5 / Q000096:biosynthesis* / Q000494:pharmacology; D002633:Chemotaxis; D003513:Cycloheximide / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D004847:Epithelial Cells / Q000187:drug effects; D006801:Humans; D007371:Interferon-gamma / Q000494:pharmacology*; D007375:Interleukin-1 / Q000494:pharmacology*; D007687:Kidney Tubules, Proximal / Q000166:cytology / Q000187:drug effects*; D007700:Kinetics; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*
chemical_list: D000906:Antibodies; D018946:Chemokine CCL5; D007375:Interleukin-1; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; D007371:Interferon-gamma; D003513:Cycloheximide