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Germinal Center Kinase-Like Kinase (GLK/MAP4K3) Expression Is Increased in Adult-Onset Still's Disease and May Act as an Activity Marker

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Germinal Center Kinase-Like Kinase (GLK/MAP4K3) Expression Is Increased in Adult-Onset Still's Disease and May Act as an Activity Marker

Der-Yuan Chen et al. BMC Med.

Abstract

Background: Germinal center kinase-like kinase (GLK, also termed MAP4K3), a member of the MAP4K family, may regulate gene transcription, apoptosis and immune inflammation in response to extracellular signals. The enhanced expression of GLK has been shown to correspond with disease severity in patients with systemic lupus erythematosus. We investigated the role of GLK in the pathogenesis of adult-onset Still's disease, which shares some similar clinical characteristics with systemic lupus erythematosus.

Methods: The frequencies of circulating GLK-expressing T-cells in 24 patients with active adult-onset Still's disease and 12 healthy controls were determined by flow cytometry analysis. The expression levels of GLK proteins and transcripts were evaluated in peripheral blood mononuclear cells by immunoblotting and quantitative PCR. Serum levels of T helper (Th)17-related cytokines, including IL-1β, IL-6, IL-17 and TNF-α, were measured by ELISA.

Results: Significantly higher median frequencies of circulating GLK-expressing T-cells were observed in patients with adult-onset Still's disease (31.85%) than in healthy volunteers (8.93%, P <0.001). The relative expression levels of GLK proteins and transcripts were also significantly higher in patients with adult-onset Still's disease (median, 1.74 and 2.35, respectively) compared with those in healthy controls (0.66 and 0.92, respectively, both P <0.001). The disease activity scores were positively correlated with the frequencies of circulating GLK-expressing T-cells (r = 0.599, P <0.005) and the levels of GLK proteins (r = 0.435, P <0.05) or GLK transcripts (r = 0.452, P <0.05) in patients with adult-onset Still's disease. Among the examined Th17-related cytokines, elevated levels of serum IL-6 and IL-17 were positively correlated with the frequencies of circulating GLK-expressing T-cells and the levels of GLK proteins as well as transcripts in patients with adult-onset Still's disease. GLK expression levels decreased significantly after effective therapy in these patients.

Conclusions: Elevated expression levels of GLK and their positive correlation with disease activity in patients with adult-onset Still's disease indicate that GLK may be involved in the pathogenesis and act as a novel activity biomarker of this disease.

Figures

Figure 1
Figure 1
The GLK expression levels in T cells from patients with adult-onset Still's diseases and healthy controls. Representative examples of flow cytometry contour plots of intracellular GLK production in CD3+ T-cells, CD4+ T-cells, and CD8+ T-cells were obtained from peripheral blood of (A) one patient with AOSD and (B) one healthy control. (C) The frequencies of circulating GLK-expressing CD3+ T-cells were obtained from 24 patients with active AOSD and 12 HC. (D) The comparison in the relative expression levels of GLK transcript between patients with AOSD and HC. (E) Immunoblot analyses of GLK expression in the lysates of peripheral blood T cells from patients with AOSD and HC. (F) The comparison in the relative expression levels of GLK protein between patients with active AOSD and HC. Horizontal bar indicates median value. *P-value was determined by Mann-Whitney U test. AOSD: adult-onset Still's disease; GLK: germinal center kinase-like kinase; HC: healthy control.
Figure 2
Figure 2
The comparison in serum levels of Th17-related cytokines from patients with active adult-onset Still's disease and healthy controls. (A) IL-1β, (B) IL-6, (C) IL-17A, and (D) TNF-α. Horizontal bar indicates median value. *P-value was determined by Mann-Whitney U test. AOSD: adult-onset Still's disease; HC: healthy control.
Figure 3
Figure 3
Correlation between GLK expression and disease activity parameters as well as cytokines in patients with adult-onset Still's disease. The correlation between the frequencies of circulating GLK-expressing T-cells and (A) disease activity score, activity parameters including (B) serum ferritin levels, (C) C-reactive protein levels and (D) soluble interleukin-2 receptor levels, and serum levels of cytokines including (E) IL-1β, (F) IL-6, (G)TNF-α and (H) IL-17A from 24 patients with adult-onset Still's disease. Correlation coefficients (γ) and P-value were obtained by the nonparametric Spearman's rank correlation test. AOSD: adult-onset Still's disease; CRP: C-reactive protein; GLK: germinal center kinase-like kinase; IL: interleukin; sIL-2R: soluble interleukin-2 receptor levels; TNF-α: tumor necrosis factor-alpha.
Figure 4
Figure 4
Changes in the levels of circulating GLK-expressing T-cells, the expression levels of GLK proteins as well as transcripts, and serum levels of soluble interleukin-2 receptor in 12 patients with adult-onset Still's disease after effective therapy. Data are presented as mean ± standard error of the mean. *P <0.005 versus before treatment, determined by the Wilcoxon signed rank test. AOSD: adult-onset Still's disease; GLK: germinal center kinase-like kinase; sIL-2R: soluble interleukin-2 receptor.

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