COMPARISON OF THE 3D MODELS OF 4 DIFFERENT HUMAN IL-7 ISOFORMS WITH HUMAN AND MURINE IL-7

The three-dimensional (3D) models of several alternatively spliced iso forms (ISO1 through ISO4) of human interleukin-7 (hIL-7) are presented . They are based on sequences of mRNA recently discovered in follicula r dendritic cells (FDC) and primary cultures of endothelial cells or s mooth muscle cells. The structures were docked to a previous model of the human IL-7 receptor, containing the IL-7 specific (IL-7R) and comm on gamma (gamma c) chain. Two different models of murine IL-7 (mIL-7) mere generated as well and docked to this receptor. For an evaluation of the structures and the possible biological role of the isoforms, th e models were analysed in detail and a series of enthalpy calculations was carried out. Compared with hIL-7, ISO1 appears to bind equally we ll to hIL-7R, but even better to the gamma(c) chain. This suggests an agonist role of ISO1, which has already been shown experimentally. The prediction that ISO2 exhibits reduced affinity to hIL-7R is supported by experiments where it had been shown to be inactive in a human test system. However, ISO2 as well as ISO3 could represent antagonists for hIL-7. Remarkably, mIL-7 appears to bind significantly less well to h IL-7R, which is in line with experimental observations that it is nob active in the human system. The sequences of the isoforms support the helix assignment made for the previous hIL-7 model.