Hyperproduction of IL-23 and IL-17 in patients with systemic lupus erythematosus: Implications for Th17-mediated inflammation in auto-immunity
Introduction
Systemic lupus erythematosus (SLE) is a prototypic systemic autoimmune disease characterized by various immunological abnormalities, including dysregulated activation of both T and B lymphocytes and subsequent polyclonal activation of circulating B lymphocytes that produces a large quantity of autoreactive antibodies [1]. It has been suggested that SLE is a T helper (Th)2-polarized disease because of its production of autoantibodies specific for self-antigens [2]. However, other studies have demonstrated that Th1 response including interferon (IFN)-γ and IL-12 were also significantly elevated in SLE patients [3], [4]. Th1 dominant immune responses have been generally considered to be pathological in autoimmune disease via the induction of inflammatory reaction [5].
IL-12, a heterodimeric cytokine of 70 kDa comprising of covalently linked p40 and p35 subunit, has been shown to be a Th1 related proinflammatory cytokine that induces IFN-γ in both innate and adaptive immunity [6], [7]. IL-12 can induce the production of IL-18 and has a synergistic effect with IL-18 on the activation of natural killer (NK) and cytotoxic T lymphocytes (CTL) [8]. IL-23 is a novel heterodimeric cytokine composed of a unique p19 subunit, and a common p40 subunit shared with IL-12. IL-23 shares similar intracellular signal transduction molecules with IL-12, therefore both cytokines exhibit some overlapping functions in promoting cellular immunity [9]. However, in contrast to IL-12, IL-23 does not promote the development of IFN-γ-producing Th1 cells, but is crucial for the expansion of a pathogenic CD4 + T cell population characterized via the production of IL-17 and IL-22 [10], [11]. IL-17 is a pleiotropic proinflammatory cytokine that enhances T cell priming and stimulates epithelial, endothelial and fibroblastic cells to produce multiple proinflammatory mediators, including IL-1, IL-6, TNF-α and chemokines [12]. In animal studies, upon adoptive transfer to naïve recipient mice, this IL-23-dependent IL-17 producing CD4 + effector T cell subset (Th17) can invade the target organ and promote the development of organ-specific autoimmune inflammation [11]. On the other hand, IL-23-deficient mice are resistant to experimental autoimmune encephalomyelitis and collagen-induced arthritis disease development [13]. A recent publication has reported elevation of IL-23 p19 in human autoimmune disease such as multiple sclerosis [14].
IL-18 was originally identified as a factor that enhances IFN-γ production in macrophages, T lymphocytes and dendritic cells [15]. Previous studies have also demonstrated the involvement of this Th1 related cytokine in initiating both innate and acquired immune responses [16], [17]. It has been demonstrated that IL-18 along with IL-12 is a potent inducer of the inflammatory mediators by T lymphocytes, causing severe inflammatory disorders in autoimmune diseases such as rheumatoid arthritis [18]. Our previous cross sectional studies have shown the elevation of plasma IL-18 concentration in SLE patients, and the plasma level correlated with SLE disease activity [19], [20], [21]. Recently, we have also reported that the derangement of CXCL10 for Th1 lymphocytes is involved in the autoinflammatory process of SLE, as exemplified by its positive correlation with disease activity and IL-18 [22]. It is evident that pro-inflammatory cytokine IL-18 could promote the downstream cytokine activation [15], [16] and IL-12-induced IFN-γ production is dependent on IL-18 [23]. However, the mechanism of IL-18 in perpetuating the production of Th1 chemokine CXCL10 and IL-23 in SLE patients has remained unknown. To dissect the involvement of IL-23 in the IL-23/IL-17 auto-inflammatory axis, we elucidated the number of circulating Th17 cells and the effect of IL-23 on the ex vivo production of IL-17 from the anti-CD3 and anti-CD28 co-stimulated peripheral blood mononuclear cells (PBMC). For better understanding of their interrelationship and immunopathological roles in SLE, we further investigated the immune response of the activated PBMC and Th17 cells by evaluating their ex vivo production of IL-12, IL-23 and IL-17 upon co-stimulation in the presence of IL-18 and examined their significance in SLE patients.
Section snippets
SLE patients, control subjects and blood samples
Eighty Chinese SLE patients (78 females, 2 males) were recruited at the rheumatology out-patient clinic of the Prince of Wales Hospital, Hong Kong. Diagnosis of SLE was established according to the 1982 revised American Rheumatism Association criteria (ARA) [24], and disease activity was evaluated by the SLE disease activity index (SLEDAI) score [25]. Active lupus disease was defined as a SLEDAI score ≥ 6 [25]. The SLE patients were divided into two groups: 40 SLE patients with renal disease
SLE patients and control subjects
Forty SLE patients with renal disease (RSLE group), 40 patients without renal disease (SLE group), and 40 sex-and age-matched control subjects (NC group) were studied. Their age, sex, duration of diagnosis, SLEDAI score, plasma urea and creatinine concentrations, and drug treatment are summarised in Table 1. Using a SLEDAI cutoff score ≥ 6, the proportions of the SLE group and RSLE group with active disease were 7.5% and 65%, respectively. Active kidney disease was shown in 67.5% of RSLE patient
Discussion
The result of this clinical study has firstly revealed significant elevations of plasma IL-23, IL-12, IL-17 and Th1 chemokine CXCL10 in SLE patients. As also observed by us, plasma IL-23, IL-12, IL-17 and CXCL10 concentrations in SLE patients did not show any correlation with the dosages of prednisolone, hydroxychloroquine and azathioprine. It has been shown that IL-23 is closely related to IL-12 with regard to both function (promotion of T cell expansion and proliferation) and structure
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These two authors contribute equally to this study.