In 1957, Isaacs and Lindenmann discovered a substance that protected cells from viral infection -they called it interferon (IFN)(430). The IFNs represent proteins with antiviral activity that are secreted from cells in response to a variety of stimuli(431). There are two types of IFNs, type I and type II, and IFN-like cytokines. To date, type I IFNs consist of eight classes: IFNα, IFNβ, IFNε, IFNκ, IFNω, IFNδ, IFNλ (limitin, IL-28A, IL-28B, and IL-29) and IFNτ(432). Type II IFN consists of IFNγ only. IFNα, IFNβ, IFNε, IFNκ, IFNω, IL-28A, IL-28B, and IL-29 are found in humans, whereas IFNδ(433), IFNτ(434), and limitin(435) are not. IFNs (Type I and Type II) were the first cytokines discovered and the first to be used therapeutically(431). Type I IFNs (mainly IFNα and
Figure 10. Multiple biological activities of IFNβ. IFNβ produced by several types of cells exerts multiple functions, including those on the innate and adaptive immune systems by acting directly to activate major figures of the immune system such as dendritic cells, T cells and monocyte/macrophages. IFNβ down-regulates the pro-inflammatory cytokines IL-1β and TNF in vitro, and it enhances sIL-1Ra and IL-10 production. In addition, other possible effects of IFNβ in MS or RA treatment include the following: inhibition of T-cell proliferation and migration, down-regulation of major histocompatibility complex class II expression, down-regulation of several adhesion molecules and enhancement of soluble adhesion molecules in serum, upregulation of transforming growth factor (TGF)-β1 and TGF-β receptor 2 expression on peripheral blood mononuclear cells. (Adapted from(7)).
IFNβ) are pleiotropic, displaying pro- and anti-proliferative, pro- and anti-apoptotic, and immuno-regulatory activities(436-440). The pleiotropic activities of IFNβ have been broadly exploited for therapeutic purposes (Figure 10) and various preparations of IFNβ have been approved for the treatment of MS(441;442). They are all effective, thought no treatment can eliminate the disease.
Similarly, IFNβ treatment is supposed to be beneficial in RA(7).
Nevertheless, taking into account the immuno-modulatory activities of IFNβ, IFNβ treatment of MS patients may lead to an adapted state of immuno-suppression that may increase the mortality risk from coincident opportunistic infection(443). There are however rare post-approval reports of opportunistic infections with IFNβ treatment. This might due to the contribution of IFNβ to the host defence against pathogens(444), including those of bacterial origin. As such, IFNβ has been reported to represent an autocrine/paracrine signal critical for robust innate immune responses elicited by LPS(445;446). This is one subject of my thesis, which results are presented and discussed in Results, section 2.
5.1. IFNβ in multiple sclerosis
Because IFNs possess antiviral properties, the rationale for the use of IFNβ in MS in the past was based on the belief that viruses may play a role in the pathogenesis of MS. At present, the current model in the pathogenesis of MS suggests that this disease has its origin in disruption of self-tolerance for CNS antigens.
While several reports have demonstrated the efficacy of IFNβ in MS(441;442), the mechanisms by which IFNβ therapy works remain unclear. As stated above, cytokine production is generally considered an important factor in determining disease activity in chronic autoimmune and inflammatory diseases. Since disease progression in MS correlates with increased levels of pro-inflammatory cytokines such as, IFNγ, IL-12, IL-1β, and TNF, and decreased levels of anti-inflammatory cytokines such as IL-10 and IL-4(179;447-450) it has been suggested that a potential way in which IFNβ might exert its beneficial effect in patients with MS was the restoration of physiologic balance between pro-inflammatory and anti/immuno-regulatory cytokines (Figure 10).
Self-tolerance disruption results in manifestation of cell-mediated autoreactivity that is mostly administrated by activated TH1 cells related with relatively high-level production of IFNγ and moderately low-level production of TH2 cytokines such as IL-4. Generally, while most studies point out a repression of the generation of TH1 cytokines following treatment with IFNβ; a distinct shift of the cytokine pattern toward a TH2-dominated profile has not been demonstrate so far(451).
IFNβ is considered as an anti-proliferative agent since its ability to inhibit the clonal expansion of pathogenic T cell(452). IFNβ might also affect the infiltration of activated T lymphocytes into the CNS ofpatients with MS that represents a significant event in MS outcome. It may as well affect the antigen presentation by preventing the IFNγ-induced up-regulation of MHC class II molecule expression on APCs(453). In addition, IFNβ might down-regulate the expression of various co-stimulatory molecules and thus possibly affects other aspects of antigen presentation.
Following their extravasations, activated CNS-antigen-primed T cells localize in proximity to microglial cells, and in such a case could potently induce the expression of IL-1β, IL-1α, TNF, and IL-6 through cell-cell contact with such CNS-adapted macrophages(377). Moreover, the great influx of non CNS–antigen specific T cells might potentiate CNS immune responses(356;357). Pre-treatment of antigen-nonspecific T lymphocytes with IFNβ prior their contact with microglial cells represses TNF production while simultaneously enhance that of IL-10(16;420). By analogy, pre-treatment of non-antigen specific-T cells with IFNβ before their encounter with monocyte/macrophages, a primary source of pro-inflammatory cytokines in CNS inflammation, repress IL-1β and TNF production(169;454). However such pre-treatment also decreases the ability of stimulated T cells to induce sIL-1Ra production in monocyte/macrophages. In contrast, IFNβ directly enhances sIL-1Ra production in the latter cells(169). Because it is unclear whether IFNβ can penetrate the BBB, it is also conceivable that comparable interactions occur as well in the systemic circulation between IFNβ-treated cells and monocytes, to result in the increased sIL-1Ra and IL-10 levels observed in the serum of patients with MS upon IFNβ therapy(182;331;455;456). Besides, IFNβ could display CNS-anti-inflammatory effect through exposure of T cells to in the systemic circulation and the subsequent entry of these cells into the CNS parenchyma where they encounter monocyte/macrophages or microglial cells.
Although the effects of IFNβ mentioned above fit well with the hypothesis that IFNβ works by induction of solely anti-inflammatory cytokines, there are conflicting reports showing that IFNβ could also up-regulate pro-inflammatory genes(457-459). This suggests that in addition to their pathological potential, pro-inflammatory mediators may have beneficial effects(460). In this context it has been observed that both TNF and IL-1 could be factors necessary for CNS repair(461;462).
Alternatively, the balance of pro- and anti-inflammatory pathways influenced by IFNβ results in an anti-inflammatory response overall. Up-regulation of inflammatory cytokines may also be related to the development of the so-called, flu-like syndrome, a common side effect of IFNβ(463).
5.2. IFNβ in rheumatoid arthritis
To date various antirheumatic drugs are only modestly and inconsistently effective. Actually whilst novel therapeutic agents that aim to neutralize the important mediators of inflammation have proven some efficiency in a subset of RA patients, these drugs are not tolerated by all patients, and only a subgroup of patients respond to them(464;465). Such limitations stimulated the search for additional effective treatments that can reduce the outcome of the disease. Subsequently, since numerous studies have demonstrated that IFNβ treatment is beneficial in MS(441;442), this has prompted studies on its therapeutic potential in RA, which is also considered to be an immune mediated disease.
In contrast to the normal physiology, where pro- and anti/immuno-inflammatory cytokines are maintained in balance, in RA this balance shifts in favor of the pro-inflammatory cytokines. The most important pro-inflammatory cytokines in RA are IL-1β andTNF(89;466). Because blockade of the effect of TNF(467) and IL-1β(468) is effective in RA, IFNβ treatment could be an interesting therapeutic strategy based on the inhibitory effects of IFNβ on the production of TNF, IL-1β, combined with the stimulatory effect on IL-10 and sIL-1Ra secretion(419;455;469). Consistent with these studies, IFNβ inhibits the production of pro-inflammatory cytokines in human monocytes activated by cell contact with stimulated T cells(169;383;419). In light of the literature showing the importance of T-cell contact-activated monocyte/macrophages in RA(4;470), IFNβ might predominantly act as an inhibitor of TNF and IL-1β production by monocyte/macrophages in the inflamed synovium. In addition, IFNβ decreases the production of IL-6, IL-8, and GM-CSF by stimulated fibroblast-like synoviocytes from osteoarthritic patients(471). Together these data suggest an anti-inflammatory effect of IFNβ on the major effector, inflammatory cell populations in rheumatoid synovial tissue, T lymphocytes, monocyte/macrophages and the fibroblast-like synoviocytes (Figure 10).
Several studies in animal models of RA (i.e. CIA) have shown noticeably beneficial effects of IFNβ treatment(471). IFNβ treatment reduced inflammation by markedly decreasing the number of inflammatory cells into the synovial tissue, and by significantly decreasing the expression of IL-6 and TNF, and to a lower extent that of IL-18 and IL-1β, while strongly upregulating that of IL-10.
IFNβ might also inhibit osteoclastogenesis, since IFNβ-treated animals display a reduced number of osteoclasts that correlates with a reduced cartilage and bone destruction. An interesting study done in rhesus monkeys with CIA demonstrated clinical improvement and decreased serum levels of C reactive protein, a well-known marker of inflammation, after IFNβ treatment, confirming the work in the mouse model showing the therapeutic potential of IFNβ for the treatment of RA(472). However,
treatment of RA patients with IFNβ has been unsuccessful so far, probably due to pharmacokinetics issues(7).