The potential role of Th17 cells and Th17-related cytokines in the pathogenesis of lupus nephritis

Abstract

T helper type 17 (Th17) cells, a novel distinct subset of Th cell, can secrete interleukin (IL)-17 in humans. Although recent data suggest that Th17 cells and IL-17 play an important role in the pathogenesis of lupus nephritis (LN), the expression of Th17-related cytokines in the kidneys of SLE patients has not been studied in detail. In the present study, we investigated circulating Th17-cell frequencies using flow cytometry and serum Th17-related cytokine levels by enzyme-linked immunosorbent assay (ELISA) in 24 LN patients (17 patients with class IV and seven patients with class V) and 12 healthy controls. We also investigated glomerular Th17-related cytokine expression in LN patients and minimal change nephropathy (MCN) patients using immunohistochemistry. Our results showed significantly higher median frequencies of circulating Th17 cells in LN patients (0.68%) than in healthy controls (0.12%, p < 0.001). Serum levels of IL-17, IL-6 and IL-23 were significantly higher in LN patients (median 7.26, 232.60 and 37.01 pg/ml, respectively) than in healthy controls (median 0.82, 34.60 and 7.42 pg/ml, respectively; all p < 0.001). Circulating Th17-cell frequencies were positively correlated with SLEDAI, renal SLEDAI and histological activity index, the degree of cellular crescent and endocapillary proliferation. Significantly higher levels of glomerular IL-17 and IL-23 expression were observed in renal biopsies from class IV LN patients as compared to those from MCN patients and normal controls. Glomerular IL-17 and IL-23 expression levels were positively correlated with renal SLEDAI and histological activity index for LN patients. Our results suggest the potential role of the IL-23/Th17 axis in the intra-renal inflammation of SLE.

Akt-Dependent Enhanced Migratory Capacity of Th17 Cells from Children with Lupus Nephritis

“…In this study, we observed increased levels of IL-6 and IL-21 in supernatants of PBMCs from children with LN. This finding is consistent with previous reports from adults with SLE (8,47). Additionally, as recently demonstrated, serum levels of IL-23 are significantly higher in children with active LN than in those with inactive LN or in controls (48).…”

“…1B). Stat3 is activated by the cytokines IL-6, IL-21, and IL-23 (24)(25)(26), which are highly expressed in patients with SLE (8,27,28). Thus, we measured the levels of IL-6 and IL-21 in supernatants from anti-CD3/CD28-activated PBMCs and found significantly higher concentrations of these cytokines in supernatants from children with LN (mean 6 SD, 22.3 6 9.4 and 26.1 6 11.4 ng/ml, respectively) than in controls (mean 6 SD, 8.6 6 2.7 and 11.3 6 4.7 ng/ml, respectively) (p , 0.0001).…”

“…The differentiation of Th17 cells depends on Stat3. Stat3 is activated in response to cytokines such as IL-6, IL-21, and IL-23, which are highly expressed in patients with SLE (8,9). Upon Stat3 activation, retinoic acid-related orphan receptor (ROR) g and RORa, which are essential transcription factors for Th17 cell differentiation, are increasingly expressed.…”

Chemokines as Potential Markers in Pediatric Renal Diseases

“…Serum soluble receptor of TNFwas elevated in 12 patients with active lupus nephritis compared with inactive SLE and healthy subjects and declined after clinical remission [42]. IL-17 and IL-23 were also elevated in serum and highly expressed in glomerulus of patients with lupus nephritis, suggesting the potential role of IL-23/Th17 axis on SLE with renal involvement [43,44].…”

New Possibilities of Pharmacotherapy for Immunoinflammatory Rheumatic Diseases: A Focus on Inhibitors of Interleukin-17

“…Увеличение концентрации ИЛ17 в сыворотках больных СКВ коррелирует с активно-стью и тяжестью иммунопатологического процесса [104][105][106]. Увеличение концентрации ИЛ6, ИЛ17, ИЛ23 в сыворотке крови и уровня циркулирующих Th17-кле-ток при СКВ коррелирует с клинической активностью заболевания и тяжестью поражения почек по данным биопсии [107]. В биоптатах почек у пациентов с волча-ночным нефритом обнаружена инфильтрация Th17-клетками [108,109], а концентрация ИЛ17 в почечной ткани коррелирует с выраженностью микрогематурии, протеинурии, сывороточным уровнем мочевины и кли-нической активностью СКВ [110].…”