ABSTRACT
Activation of STAT1 and the IFN-gamma response are thought to be mediated exclusively through the Y440 motif of the human IFNGR1 receptor subunit. Contrary to this accepted dogma, here it is shown that IFNGR1 with a mutant (Y440F) motif, when stably expressed in IFNGR1-negative human fibroblasts at levels similar to wild type, can sustain a substantial IFN-gamma response. The mutant receptor supports selective induction of IFN-gamma-inducible genes but is notably defective in the CIITA, class II HLA, suppressor of cytokine signaling and antiviral responses. Remarkably, similar selective defects are observed in human fibrosarcoma cells expressing a mutant JAK1. The phenotypes are novel and appear distinct from those observed in response to the inhibition of known additional pathways. Data from different cell types further emphasizes the importance of cellular background in determining the response.
Subject(s)
Receptors, Interferon/physiology , Signal Transduction/physiology , Fibroblasts/chemistry , Gene Expression Regulation/drug effects , Humans , Interferon-gamma/pharmacology , Janus Kinase 1 , Mutation , Nuclear Proteins/physiology , Phosphatidylinositol 3-Kinases/physiology , Phosphorylation , Protein-Tyrosine Kinases/physiology , Receptors, Interferon/analysis , STAT1 Transcription Factor/physiology , STAT3 Transcription Factor/physiology , Trans-Activators/physiology , Interferon gamma ReceptorABSTRACT
Signaling through Janus kinases (JAKs) and signal transducers and activators of transcription (STATs) is central to the responses to the majority of cytokines and some growth factors, including the interferons (IFNs) and the IL-6 family of cytokines. The biological responses to stimulation through the widely distributed IL-6 and IFN-gamma receptors are, however, completely different. Remarkably, it is shown here that, in mouse embryo fibroblasts lacking STAT3, IL-6 mediates an IFN-gamma-like response including prolonged activation of STAT1, the induction of multiple IFN-gamma-inducible genes, the expression of class II MHC antigens, and an antiviral state. Normal cells exposed to IL-6 thus require a STAT3-dependent function(s) to down-regulate STAT1 activity and prevent an IFN-gamma-like response. The data encourage the view that the very disparate IFN-gamma and IL-6 JAK/receptor complexes mediate a common set of generic or "core" signals which are subject to STAT3-dependent modulation to provide IL-6 specificity. The switching of one cytokine response to one closely mimicking another as a result of the loss of a single signaling component has profound implications, for example, for the interpretation of the phenotypes of knockout mice and for the clinical use of inhibitors of signaling.
