Structure-function analysis of murine interferon-alpha subspecies

IFN has been defined as an antiviral agent, but, in addition, displays antiproliferative and immunomodulatory activities. It can be divided in three distinct subtypes: a, ~ and ~ . IFN-a is encoded by a multigene family and comprises a group of structurally very related proteins. Despite this strong homology there exists a considerable variation in biological activity between the various IFN-a proteins. these proteins are an ideal subject for a function analysis. In this thesis data As a consequence, detailed structureare presented on structure-activity relationships of several Mu IFN-a subspecies. Normally cells do not express IFN. They start t9 secrete IFN molecules after exposure to an inducing agent, for instance a virus. In Chapter 2 molecular details. with regard to the regulation of IFN expression are discussed. After IFN has left the cell it binds to a high affinity receptor situated on a neighboring cell or on the producing cell itself. This IFNreceptor interaction initiates a cascade of events, which ultimately leads to modulation of the expression of at least 25 genes (Chapter 3). It is not known as yet which part of the IFN protein is involved in interaction with the receptor and mediates biological activity. To elucidate this question several groups have constructed hybrid and mutant IFN molecules. Subsequently, the biological activities (mainly antiviral) of the modified IFNs have been compared to those of the parental proteins. our current knowledge on structure-activity relationships of IFN proteins is, for a great deal, based on studies performed with Hu and Mu IFN-a proteins. An overview of the data obtained in this field is presented ,in Chapter 4. In the same chapter structural characteristics of the regions found to be responsible for changes in antiviral activity of modified !FN proteins are discussed ,and the possible location of receptor binding sites is suggested.