SLE is an autoimmune disease characterized by multiple autoantibodies against self-directed antigens and multisystemic involvement. PGRN is an autocrine growth factor contains seven and a half repeats of a cysteine-rich motif in the order P–G–F–B–A–C–D–E, in which G–E are full repeats and P is the half-motif . PGRN is mainly expressed in epithelial cells, immune cells, neurons , and chondrocytes . Moreover, high levels of PGRN expression are found in a variety of human cancers . Several studies have revealed that PGRN plays an important role in many pathological processes, including early embryonic development, wound healing and inflammation [8–13]. PGRN also functions as a regulator of cartilage development and degradation , and PGRN exhibites higher affinity for TNF receptors (TNFR), especially TNFR2 when compared with TNF-α . In this study, the level of PGRN and TNFR was also increased in SLE patients. PGRN acts as a powerful antagonist of TNF-α signaling and disturbs the binding of TNF-α and TNFR . Previous researches showed that PGRN convectively suppressed TNF-α-mediated activation of neutrophil granulocyte  and degradation of chondrocyte . In summary, PGRN, which binds directly to TNFR, is involved in many physiological and pathological functions. It also plays a critical role in the pathogenesis of inflammatory arthritis in mice. Up-regulation of PGRN has been reported in hemotherapy-induced amenorrhea (CIA) . Our present study showed that the level of PGRN in peripheral blood was upregulated in both pre-and post-treatment SLE patients compared to healthy controls, which is in accordance with the above reports. TNF shows different physiologic and pathogenic effects in autoimmune diseases . TNF has both immuno-suppressive and pro-inflammatory effects in SLE patient. TNF is highly over expressed in both sera and renal tissue of the lupus mice and the levels of TNF is correlated with the degree of inflammatory organ disease. As the antagonist of TNF-α, PGRN was over-expression in SLE sufferer. So we think that PGRN is also a pathogenic factor of SLE. Besides, active SLE patients have higher PGRN serum levels compared with that treated with prednisone, which lead us to speculate that PGRN expression is correlated with disease activity.
Serine proteases can digest PGRN into individual granulin units, which are actually pro-inflammatory and can neutralize the anti-inflammatory effects of intact PGRN [11, 12]. Both neutrophil elastase and PR3 digest PGRN to liberate granulin units [11, 12]. In our study, we also found that the level of PR3 is higher in SLE patients both before and after prednisone treatment. Therefore the increases of PGRN detected in serum maybe result from the upregulation of individual PGRN units. PGRN may function as a pro-inflammatory factor. Further studies are needed to investigate the form of PGRN in the serum of SLE patients. In post- treatment SLE group, PGRN expression was lower than that in pre-treatment group, but the level of PR3 showed no change. Therefore, we suppose that PGRN could be used as a molecular marker of SLE.
In the pre-treatment group, both IL-6 and ds-DNA are higher than the post-treatment group and control group. They are both correlated of linear with the levels of PGRN (P < 0.05). IL-6 has been identified as an important factor in the pathogenesis of SLE . The biological activities of IL-6 were diverse, inducing differentiation of B cells in plasma cells and production of IgG . IL-6-deficient Mrl/lpr mice show a delayed onset of lupus nephritis and prolonged survival . Murine lupus models indicate the involvement of IL-6 in B-cell hyperactivation and the onset of SLE [18, 19]. The upregulation of IL-6 levels we observed was in accordance with the above reports. IL-6 is also associated with lupus nephritis and joint damage [20–22]. As IL-6 exerts both systemic and local effects, IL-6 targeting therapy has been proved to be effecient in inflammatory autoimmune diseases . It has been shown that patients with active SLE have increased serum level of IL-6, which was correlated with disease activity or anti-dsDNA levels [20, 21]. Therefore, we analyzed the relationship between IL-6 and PGRN levels and showed that they are correlated. Development of SLE is a very complex process. Therefore, we need more objective information to assess the disease activity in order to better guide clinical diagnosis. PGRN will be a very useful factor for the diagnosis of SLE. Therefore, PGRN was of value not only in the diagnosis, but also in the assessment of SLE severity.
GCs are powerful anti-inflammatory and immunosuppressive agents. They are widely used in systemic autoimmune diseases, such as SLE, dermatomyositis and other systemic diseases . GCs exert their anti-inflammatory and immunosuppressive roles by two different mechanisms: the genomic pathway and the non-genomic pathway . The interaction of GCs and GC receptor (GR) complex modulates gene expression to inhibit the transfer of leucocyte to inflammation site and damage the function of leucocyte, fibroblast and endothelial cells . GCs reduce the synthesis of pro-inflammatory cytokines, such as IL-2, IL-6, TNF-α and prostaglandins (PGs) [24, 25]. In SLE patients, disorder cytokine production induces immunodeficiency and leads to tissue inflammation and organ damage, such as diffuse proliferative lupus nephritis . PR3 is involved in the development of a variety of autoimmune diseases, such as Wegener’s granulomatosis .
Our present study showed that the levels of PGRN, IL-6, TNFR, TNF-α and anti-dsDNA decreased after administration of large doses of prednisone 1 mg/kg/day for fourteen twenty-one consecutive days, and this was consistent with the above reports. In a word, the present study demonstrated that PGRN is up-regulated in both active and GC-treated SLE patients. PGRN was concerned to be correlated with the disease activity of SLE. Academic studies still needed to understand the precise mechanisms of PGRN in regulating SLE. Since TNFR signaling is involved SLE processes, antagonists of the TNF/TNFR pathway may lead to a new therapeutics for this disease. PGRN may be used as a diagnostic marker of systemic lupus erythematosus.