In this study, we report for the first time an association between increased levels of serum resistin and the disease activity of patients with inflammatory myopathies, particularly in anti-Jo-1 positive and dermatomyositis patients. Additionally, we found that the expression of resistin is up-regulated in muscle tissues of patients with inflammatory myopathies. Lastly, we found that resistin may contribute to the increased production of pro-inflammatory cytokines in mononuclear infiltrates, thus indirectly participating in muscle tissue pathology.
Although resistin was initially associated with metabolic disorders, increased levels of resistin and its positive correlation with inflammatory markers and disease activity have been previously demonstrated in patients with rheumatoid arthritis (RA) [4
]. In a study by Almehed and colleagues, serum resistin levels did not differ between patients with systemic lupus erythematosus (SLE) and healthy controls [21
]; whereas in another study, SLE was independently associated with higher resistin levels [22
]. Moreover, in both studies, the levels of resistin positively correlated with inflammatory markers, disease-specific measures and renal dysfunction. In our study, we observed a strong correlation between higher levels of serum resistin and CRP and, most importantly, we observed an association with the global disease activity assessment of inflammatory myopathy. Importantly, we found that serum resistin levels were strongly associated with CRP and global disease activity, and a trend was also observed towards correlation between resistin levels and myoglobin in patients with myositis-specific anti-Jo-1 antibody in contrast to anti-Jo-1 negative patients. Furthermore, resistin levels significantly correlated with global disease activity and muscle enzymes in DM patients. These results are in line with the abovementioned findings, further supporting an association between resistin and autoimmune rheumatic diseases [4
]. On the other hand, serum resistin levels did not correlate with muscle weakness. Thus, it could be hypothesized that serum resistin concentration may reflect global disease activity, including extramuscular organ involvement, rather than functional impairment in inflammatory myopathies. However, disease specific mechanisms can be suggested.
Recently, we demonstrated the increased expression of resistin in immune cells of RA synovial tissue [19
]. In the present study, we consistently observed the up-regulation of resistin in the mononuclear cells of inflammatory infiltrates surrounding vessels and muscle fibres in patients with inflammatory myopathies. In contrast, there was no expression of resistin in control non-inflammatory muscle tissue. Importantly, a majority of samples from DM and myositis patients showed resistin staining in regenerating muscle fibres, perhaps implicating a contribution of the muscle tissue to the inflammatory process or influence of resistin on regenerating/immature muscle precursors in the pathogenesis of myositis. The presence of fibre degeneration and regeneration is a typical histopathological picture of inflammatory myositis. Initially, muscle repair is characterized by inflammation and degeneration of damaged muscle tissue. It is followed by activation, proliferation and differentiation of myogenic, so-called satellite cells with subsequent fusion and formation of multinucleated muscle fibres. This process requires a crosstalk between immune and muscle cells, including secreted factors [23
]. In fact, at the moment it is not possible to distinguish the features of the inflammatory myositis that promote the injury from those that cause muscle regeneration and repair [25
]. Accordingly, the role of resistin in the pathology of muscle tissue in myositis is underpinned by its association with parameters of disease activity in the group of patients with myositis associated autoantibody Jo-1. As we found increased systemic and local levels of resistin in inflammatory myopathies, we examined the effect of resistin on muscle and mononuclear cells in vitro
. In line with previous reports [8
], we found that resistin induces expression and synthesis of several proinflammatory mediators in mononuclear cells, thus possibly contributing to muscle tissue pathology. As demonstrated previously, IL-1, IL-6, MCP-1, as well as TNFα, are increased in myositis muscle tissues and contribute to disease pathogenesis [27
]. However, these cytokines may have dual function and may not only contribute to muscle tissue damage, but also to the regeneration and healing of the muscle tissue [25
]. Considering the ambivalent role of several mediators in inflammatory myositis, dual functions of resistin may be suggested. In this regard, we observed a trend towards the reduced synthesis of the cytotoxic enzymes perforin and granzyme in resistin-stimulated immune cells.
It has been shown that several Toll-like receptors (TLRs) are expressed in immune cells but are not present in the muscle fibres of patients with inflammatory myopathies [31
]. A recent study demonstrated that a TLR4 receptor mediates the proinflammatory effects of resistin in human cells [32
]. Therefore, we assume that the lack of resistin-associated effects on myocytes in our study may be due to the absence of TLR4 receptors on the surface of these cells. That being said, resistin did not modulate the expression of several interferon (IFN)-α/β induced genes that have been recently observed in tissue of patients with inflammatory myopathies [33
]. Interestingly, immature muscle precursors in myositis biopsy tissues have been recently demonstrated as an important source of IFN-β, which was, however, mediated by TLR-3 activation [34