Role of Differential Expression of Interferon Receptor Isoforms on the Response of Multiple Sclerosis Patients to Therapy with Interferon Beta

The cytokine interferon (IFN)-beta 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-beta exerts its biological effects through interaction with the IFN-alpha/-beta-receptor (IFNAR), which then activates several transcription factors. IFNAR is composed of 2 chains, IFNAR-1 and IFNAR-2, which associate with IFN-beta 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-beta therapy and of its clinical and biological outcomes in IFN-beta-treated patients.