Pharmac. Ther. Vol. 52, pp. 149-157, 1991 0163-7258/91 $0.00+ 0.50 Printed in Great Britain. All rights reserved © 1992PergamonPresspie Associate Editor: S, PESTKA TRANSMEMBRANE SIGNALLING BY INTERFERON-0t L. M. PFEFFER* and O. R. COLAMONICI~ *Department of Pathology, University of Tennessee Medical Center, 800 Madison Avenue, Memphis, TN 38163, U.S.A. tDepartment of Medicine, Section of Hematology/Oncology, University of Chicago, 5841 S. Maryland Avenue, Chicago, IL 60637, U.S.A. Abstract--Human leukocyte interferon (IFN<t) binds to discrete cell surface receptors on target cells, and thereby alters gene expression. Transmembrane signaling by IFN<t involves the production of DAG without an increased intracellular free calcium concentration, and the subsequent activation of calcium-in- dependent isoforms of PKC (fl and E). Selective PKC inhibitors (H-7 and staurosporine) can block the ability of IFN-~t to activate the transcription of a distinct set of genes, called the IFN-stimulated genes (ISG), and to protect cells against viral infection. IFN-~t also induces the rapid changes in protein phosphorylation, which may include latent transcription factors for ISGs. CONTENTS 1. Introduction 2. Signal Transduction Pathways 2.1, Rapid changes in lipid hydrolysis and DAG in response to IFN<t signalling 3. Interferon-~ Activation of PKC 4. Specificity of Signalling for Different Ligands 5. Transcriptional Activation by IFN<t and the Role of DNA-binding Factors 6. Role of Arachidonic Acid Metabolites in IFN-~t Signal Transduction 6.1. Rapid protein phosphorylation in response to IFN-~t 7. Summary Acknowledgements References 149 150 151 151 152 153 154 154 155 155 155 1. INTRODUCTION Interferons (IFNs) are cellular secretory proteins that were originally identified on the basis of broad antiviral activity. IFNs are now recognized as mem- bers of the cytokine family that induce a variety of physiological responses, among which are the inhi- bition of cell proliferation and the modulation of the immune system (Pfeffer, 1987; Pestka et al., 1987). Interferons elicit these effects by binding to specific receptors on the surface of target cells and transduc- ing a signal to the nucleus that results in rapidly and transiently inducing or up-regulating some genes and down-regulating others (Aguet, 1980; Rubinstein and Orchansky, 1986; Pfeffer, 1987; Branca, 1988; Langer and Pestka, 1988). These alterations in some 50--100 cellular proteins are responsible for the IFN- induced alterations in cell behavior. The three types of IFNs, IFN<t, -fl, and -?, are defined by the cellular source of their production and are distinguished by their immunoreactivity. IFNs are classified as either type I or II on the basis of the mechanism that induces their synthesis. Type I IFN (IFN-~ and -1~) are produced by nearly all cells in response to viral infections, whereas type II IFN (IFN-),) is produced by lymphocytes in response to mitogenic or antigenic stimuli. Type I IFNs compete with each other for cellular binding and thus apparently share the same receptors. However, the receptor(s) for type I IFN is distinct from the receptor for type II IFN (Branca and Baglioni, 1981). The human gene for the type I IFN receptor is located on chromosome 21, while the gene for type II receptor is on chromosome 6 (Langer and Pestka, 1988). In addition, a component for biologic activity of type II IFN is contributed by chromosome 21 (Jung et al., 1987; Langer and Pestka, 1988). Furthermore, although a majority of biological effects are induced by all IFNs, some (i.e. induction of specific proteins) are induced by type-I IFN selectively, and others by type II IFN (Revel and Chebath, 1986; Pestka et al., 1987). Although IFN-~t binding to cell surface receptors is an important event, IFN binding alone is not suffi- cient to induce antiviral and antiproliferative activity. Several IFN-resistant cell lines, including IFN- resistant subclones of IFN-sensitive parental cell lines, have been characterized that display significant levels of high affinity IFN receptors as compared to 149