Role of differential expression of interferon receptor isoforms on the response of multiple sclerosis patients to therapy with interferon beta.
The cytokine interferon (IFN)-β is successfully used in the treatment of multiple sclerosis. However, some patients fail to respond to therapy, probably due to different biological patterns that are of importance in influencing clinical response. A common mechanism involved in the modulation of responsiveness to cytokine is represented by regulation of their receptor expression through autocrine-ligand-mediated loops. Mechanistically, IFN-β exerts its biological effects through interaction with the IFN-α/-β-receptor (IFNAR), which then activates several transcription factors. IFNAR is composed of 2 chains, IFNAR-1 and IFNAR-2, which associate with IFN-β to form a ternary complex. The major ligand-binding subunit is IFNAR-2 and it exists in 3 mRNA splice variants, resulting in 2 transmembrane (IFNAR-2b and IFNAR-2c) isoforms and a soluble (IFNAR-2a) one. On the contrary, from normal cells only one IFNAR-1 isoform, with transcriptional capacity, was identified. In the past decades, considerable information has accumulated pertaining to the downregulation of the IFNAR complex in IFN-treated patients, but only a few studies have investigated the molecular events involved in this phenomenon. The intent of the present review is to place this receptor downregulation in the context of IFN-β therapy and of its clinical and biological outcomes in IFN-β-treated patients.
Gilli
Francesca
F
SCDO Neurology 2-Regional Reference Centre for Multiple Sclerosis (CReSM), Neuroscience Institute of the Cavalieri Ottolenghi Foundation, University Hospital S. Luigi Gonzaga, Ottolenghi, Orbassano (Torino), Italy. francesca.gilli@fastwebnet.it
D005786:Gene Expression Regulation / Q000235:genetics*; D006801:Humans; D016899:Interferon-beta / Q000627:therapeutic use*; D009103:Multiple Sclerosis / Q000188:drug therapy* / Q000235:genetics*; D020033:Protein Isoforms / Q000235:genetics; D053633:Receptor, Interferon alpha-beta / Q000235:genetics*
D020033:Protein Isoforms; D053633:Receptor, Interferon alpha-beta; D016899:Interferon-beta