As found for most cytokines and growth factors, the actions of IFNs are mediated by an interaction with specific cell surface receptors. All of the type I IFNs share the same receptor complex, whereas type II IFN binds to a distinct receptor, as do the interferon-like cytokines IL-28A, IL-28B and IL-29.³ The receptor complex for the type I IFNs consists of two chains, IFNAR1 and IFNAR2,^4,5 whose genes are clustered on chromosome 21. Two splice variants of IFNAR1 have been identified in cell lines,^6–8 but one is probably an artefact or an aberrant transcript found only in particular tumour cell lines.⁹ In contrast, IFNAR2 is expressed in vivo in three different isoforms, which are generated by alternative splicing, exon skipping and differential usage of polyadenylation sites and differ in the length of the carboxyterminal tail and in the signalling capacity.¹⁰ IFNAR2.2 full-length is the functional isoform, and is made up of 487 amino acids, 251 of which lie in the cytoplasmic portion.^11,12 IFNAR2.1 short isoform has a truncated cytoplasmic tail of 67 residues, and is partially impaired in the signalling response^11–13 or incapable of complete signalling.¹⁴ IFNAR2.3, lacking both the transmembrane and intracytoplasmic domains, is a soluble receptor isoform that has been found in different body fluids.^1,15 Depending on its relative concentration, the stability of its binding with the ligand and the rate of discharge, it may be regarded either as a competitive antagonist, acting as a molecular decoy, or, indirectly, as an agonist, as it protects bound IFN-β from degradation and prolongs its half-life.¹⁶ The process of receptor activation involves the initial binding of type I IFNs to the IFNAR2 subunit¹⁷ followed by the recruitment of the IFNAR1 subunit, with subsequent commencement of a signalling cascade¹⁸ that leads to catalytic activation of associated tyrosine kinase 2 (Tyk2) and Janus tyrosine kinase 1 (Jak1), which in turn phosphorylate signal transducer and activator of transcription (STAT)- 1 and STAT-2 (although activation of STAT-3, STAT-4, STAT-5 and STAT-6 has also been reported).^19–22 All of these phenomena ultimately activate the IFN-stimulated response elements (ISRE) of the gene promoter,²³ which in turn regulate the transcription of the several genes responsible for the IFN-mediated effects.

Interferon-β Treatment in Multiple Sclerosis
Multiple sclerosis (MS) is an immune-mediated demyelinating disease of the central nervous system characterised by bouts of neurological symptoms (or relapses) and increasing disability. Although this disease was first described in the 1800s,²⁴ therapies have become commercially available only during the last 15–20 years. IFN-β was the first drug to be approved and, despite several novel therapies being tested and/or recently introduced, it still provides the mainstay of MS disease-modifying therapies. All of the three recombinant IFN-β preparations currently registered for MS therapy – Rebif (IFN-β-1a; Ares-Serono, Geneva, Switzerland), Avonex (IFN-β-1a; Biogen, Cambridge, MA, US) and Betaferon (IFN-β-1b; Schering AG, Berlin, Germany) – have been shown to positively modulate disease activity (relapses and active lesions apparent on magnetic resonance imaging), while therapy advantages on disease progression (disability and total lesion burden) are less consistent.