Unrestricted Agonist Activity on Murine and Human Cells of a Lipopeptide Derived from IFN-γ

We describe the isolation of a synthetic agonist of IFN-γ (L-mIFN-γ-Ct) active on mouse and human cells. Its biological activity is the result of the ability of the C-terminal extremity of murine IFN-γ to interact with the intracellular part of IFNγ-R and the observation that the modification of peptides by a palmitic acid enables their cytoplasmic delivery. L-mIFN-γ-Ctstimulated murine cells exhibited an increase in MHC class II molecules and FcγRII/III expression and conferred protection against viral lysis. Unresponsiveness to L-mIFN-γ-Ctof cells recovered from IFNγ-R α-chain knockout mice indicated the involvement of IFNγ-R in the biological activities observed. Induction of VCAM-1, ICAM-1, and HLA-DR expression on human cells stimulated with L-mIFN-γ-Ctdemonstrated an abrogation of species specificity. These results describe the development of a new synthetic agonist of IFN-γ, which substitutes for the native cytokine in any IFN-γ responsive cells, by acting intracellularly on IFN-γR.