Unrestricted agonist activity on murine and human cells of a lipopeptide derived from IFN-gamma

We describe the isolation of a synthetic agonist of IFN-gamma (L-mIFN-gamma -CT) active on mouse and human cells. Its biological activity is the result of the ability of the C-terminal extremity of murine IFN-gamma to interact with the intracellular part of IFN gamma-R and the observation that the mo dification of peptides by a palmitic acid enables their cytoplasmic deliver y. L-mIFN-gamma-CT stimulated murine cells exhibited an increase in MHC cla ss II molecules and Fc gamma RII/III expression and conferred protection ag ainst viral lysis. Unresponsiveness to L-mIFN-gamma-CT of cells recovered f rom IFN gamma-R alpha-chain knockout mice indicated the involvement of IFN gamma-R in the biological activities observed. Induction of VCAM-1, ICAM-1, and HLA-DR expression on human cells stimulated with L-mIFN-gamma-CT demon strated an abrogation of species specificity. These results describe the de velopment of a new synthetic agonist of IFN-gamma, which substitutes for th e native cytokine in any IFN-gamma responsive cells, by acting intracellula rly on IFN-gamma R. (C) 1998 Academic Press.