4Embracing novel cytokines in RA – complexity grows as does opportunity!
Section snippets
IL-17 Biology in RA
In the past few years, there has been increasing evidence that cytokines of the IL-17 family (and, in particular, IL-17A produced by the T helper (Th17)-cell axis) play an important role in RA pathogenesis. Initially, the cDNA of human IL-17 was cloned from a library of CD4 + T cells and stimulation of peripheral blood T cells was shown to induce IL-17 [1], [2]. IL-17 stimulates epithelial, endothelial and fibroblast type cells to produce cytokines such as IL-6 and IL-8, together with matrix
IL-23/IL-12p40 Biology in RA
The cytokine IL-23 is a heterodimeric cytokine composed of a p19 and a p40 subunit; the latter is shared with IL-12 (p35/p40), which drives naïve T cells into Th1 cells. IL-23 is produced by activated dendritic cells and macrophages and seems to be important in induction and maintenance of Th17 cells. Expression in RA synovial fluid is controversial with groups reporting low and others very high levels. Interestingly, in synovial tissue, bioactive IL-23 seems to be present only in low levels
TWEAK
TWEAK (TNF-like weak inducer of apoptosis) is a member of the TNF superfamily of cytokines and shares a high level of homology with other TNF cytokine members[24] but signals through its own receptor TWEAKR (TNFRSF12A). It was first described in1997 and was shown to be expressed in various tissues, including brain, heart and spleen[24] but was undetectable in unstimulated peripheral blood mononuclear cells (PBMCs) [25]. Stimulation of human monocytes with interferon (IFN)γ induces secretion of
GM-CSF
GM-CSF signals through a heterodimer receptor complex comprising of an α-ligand specific sub-unit and a βc sub-unit (shared with IL-3), which allows high affinity binding of GM-CSF. GM-CSF has been implicated in the regulation of neutrophil, macrophage and dendritic cell production and differentiation from bone-marrow precursors [33], [34]. GM-CSF is has been detected within the synovium of patients with RA[35], [36] and the concentration of GM-CSF is elevated in the plasma of patients with RA
BLyS (BAFF) and APRIL
B-cell depletion by the anti-CD20 targeted monoclonal antibody, rituximab, has been successful in ameliorating disease in a proportion of RA patients. As such, B-cell depletion is now a favourable strategy for the treatment of inflammatory arthropathies and other auto-immune conditions alike. BLyS (B-lymphocyte stimulator) and APRIL (A Proliferation Induced Ligand) are both members of the TNF superfamily of cytokines. They are potent regulators of B-cell survival and differentiation, which are
Adipocytokines
Adipocytokines, or adipokines, are bioactive proteins mainly produced by white adipose tissue that are known to regulate glucose and lipid metabolism, energy homeostasis and cardiovascular function. In addition, they can regulate immune and inflammatory responses [58]. Adipokine biology may be of particular interest in understanding the accelerated cardiovascular disease found in RA patients [59]. Furthermore, local fat pads within or surrounding joints have been demonstrated to secrete
Leptin
Leptin is a peptide hormone mainly produced by adipocytes, encoded by the gene obese (ob) in mice and LEP in humans, which regulates body weight by inhibiting food intake. It belongs to the class I cytokine superfamily and can modulate many inflammatory and immune responses, including inducing T-cell activation, driving a Th1 response and multiple effects on monocytes/macrophages, neutrophils, basophils, eosinophils, natural killer (NK) and dendritic cells (reviewed in Matarese et al [61].).
Adiponectin
Adiponectin is protein released by adipocytes with anti-diabetic and anti-inflammatory properties. It can exist as a trimer, hexamer or larger multimer with 12–18 subunits and circulates at very high plasma concentrations. Patients with RA showed considerably higher plasma concentrations of adiponectin than osteoarthritis (OA) patients[74] or healthy controls [62], and these levels: (1) correlate with the severity of RA evaluated by extent of joint destruction [75], (2) negatively correlate
Resistin
Resistin (also known as FIZZ3) is a dimeric protein named for its ability to induce insulin resistance in mice and is found in adipocytes, macrophages and other cell types. However, many contradictory findings have been found in both mice and humans complicating this field of research with the pro-inflammatory effects appearing dominant to the insulin resistance-inducing effects in humans. In RA, some studies have shown resistin levels to be elevated both in plasma and in synovial fluid of RA
Visfatin
Visfatin, also known as pre-B-colony enhancing factor (PBEF), is an adipokine originally shown as a growth factor for B lymphocyte precursors. Plasma visfatin levels are increased in patients with RA [62], [91], [92], and mRNA levels of visfatin are significantly increased in synovial tissues, PBMC and granulocytes of RA patients [92]. RA synovial tissue specimens hybridised in situ with specific antisense RNA probes for visfatin mRNA demonstrated that synovial fibroblasts were the major
Conclusions
The plethora of potential cytokine targets in RA synovium begs the obvious question as to how best they can be prioritised and thereafter targeted. The current approach remains the identification of a target followed by clarification of its potential functions ex vivo in combination with in vivo targeting in relevant animal models. Increasingly, a more sophisticated approach based on systems biology base analyses of patient phenotype and genotype, together with prior therapeutic history, may be
Acknowledgements
AJ Hueber is supported by a German Research Foundation (DFG) fellowship. AM Miller is supported by a BHF Intermediate Basic Science Research Fellowship (FS/08/035/25309). This work was also supported by the Arthritis Research Campaign (ARC – UK).
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These authors contributed equally to this work.