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Involvement of TLR7 MyD88-dependent signaling pathway in the pathogenesis of adult-onset Still's disease.

Chen DY, Lin CC, Chen YM, Lan JL, Hung WT, Chen HH, Lai KL, Hsieh CW - Arthritis Res. Ther. (2013)

Bottom Line: Significantly higher median frequencies of TLR7-expressing pre-mDCs and mDCs were observed in AOSD patients (65.5% and 14.9%, respectively) and in SLE patients (60.3% and 14.4%, respectively) than in HC (42.8% and 8.8%, respectively; both P <0.001).TLR7 ligand (imiquimod) stimulation of PBMCs resulted in significantly enhanced levels of interleukin (IL)-1β, IL-6, IL-18 and IFN-α in AOSD and SLE patients.The overexpression of TLR7 MyD88-dependent signaling molecules may be a common pathogenic mechanism for both AOSD and SLE.

View Article: PubMed Central - HTML - PubMed

ABSTRACT

Introduction: The objective of this study was to investigate the potential role of the Toll-like receptor 7 (TLR7) signaling pathway in the pathogenesis of adult-onset Still's disease (AOSD).

Methods: Frequencies of TLR7-expressing precursor of myeloid dendritic cells (pre-mDCs) and mDCs in 28 AOSD patients, 28 patients with systemic lupus erythematosus (SLE) and 12 healthy controls (HC) were determined by flow cytometry analysis. Transcript and protein levels of TLR7 signaling molecules in peripheral blood mononuclear cells (PBMCs) were evaluated by quantitative PCR and western blotting respectively. Serum cytokines levels were measured by ELISA.

Results: Significantly higher median frequencies of TLR7-expressing pre-mDCs and mDCs were observed in AOSD patients (65.5% and 14.9%, respectively) and in SLE patients (60.3% and 14.4%, respectively) than in HC (42.8% and 8.8%, respectively; both P <0.001). Transcript and protein levels of TLR7-signaling molecules, including MyD88, TRAF6, IRAK4 and IFN-α, were upregulated in AOSD patients and SLE patients compared with those in HC. Disease activity scores were positively correlated with the frequencies of TLR7-expressing mDCs and expression levels of TLR7 signaling molecules in both AOSD and SLE patients. TLR7 ligand (imiquimod) stimulation of PBMCs resulted in significantly enhanced levels of interleukin (IL)-1β, IL-6, IL-18 and IFN-α in AOSD and SLE patients. Frequencies of TLR7-expressing mDCs and expression levels of TLR7 signaling molecules significantly decreased after effective therapy.

Conclusions: Elevated levels of TLR7 signaling molecules and their positive correlation with disease activity in AOSD patients suggest involvement of the TLR7 signaling pathway in the pathogenesis of this disease. The overexpression of TLR7 MyD88-dependent signaling molecules may be a common pathogenic mechanism for both AOSD and SLE.

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Serum cytokines levels and the fold-increases of supernatant cytokines levels after stimulation with the Toll-like receptor (TLR)7 ligand. The comparison in serum levels of cytokines, including IL-1β (A), IL-6 (B), IL-18 (C), TNF-α (D), and IFN-α (E) among patients with adult-onset Still's disease (AOSD), patients with systemic lupus erythematosus (SLE), and healthy controls (HCs). To explore the functional role of TLR7, we examined the fold-increases of supernatant cytokines levels, including IL-1β (F), IL-6 (G), IL-18 (H), TNF-α (I), and IFN-α (J) after stimulation with the TLR7 ligand (imiquimod 5 μg/mL) in AOSD patients, SLE patients, and HCs. The horizontal line indicates the median value for each group. The P-value was determined by the Mann-Whitney U-test.
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Figure 3: Serum cytokines levels and the fold-increases of supernatant cytokines levels after stimulation with the Toll-like receptor (TLR)7 ligand. The comparison in serum levels of cytokines, including IL-1β (A), IL-6 (B), IL-18 (C), TNF-α (D), and IFN-α (E) among patients with adult-onset Still's disease (AOSD), patients with systemic lupus erythematosus (SLE), and healthy controls (HCs). To explore the functional role of TLR7, we examined the fold-increases of supernatant cytokines levels, including IL-1β (F), IL-6 (G), IL-18 (H), TNF-α (I), and IFN-α (J) after stimulation with the TLR7 ligand (imiquimod 5 μg/mL) in AOSD patients, SLE patients, and HCs. The horizontal line indicates the median value for each group. The P-value was determined by the Mann-Whitney U-test.

Mentions: As shown in Figure 3A-E, significantly higher median levels of serum IL-1β, IL-6, IL-18, and IFN-α in patients with active AOSD (19.65 pg/mL, IQR 3.55 to 32.79 pg/mL, 984.98 pg/mL, IQR 409.24 to 2064.92 pg/mL, 2,613.44 pg/mL, IQR 983.04 to 5,765.09 pg/ml, and 45.02 pg/mL, IQR 26.27 to 91.26 pg/mL, respectively) and higher median levels of serum IL-6, IL-18, and IFN-α in active SLE patients (405.48 pg/mL, IQR 330.32 to 945.83 pg/mL; 605.10 pg/mL, IQR 539.52 to 708.98 pg/mL, and 43.21 pg/mL, IQR 16.23 to 49.12 pg/mL, respectively) were observed when compared to those in healthy controls (2.61 pg/mL, IQR 2.49 to 5.22 pg/mL, P <0.05 for IL-1β; 85.78 pg/mL, IQR 33.38 to 249.22 pg/mL, P <0.001 and P <0.005 for IL-6; 322.69 pg/mL, IQR 222.50 to 424.03pg/mL, P <0.001 and P <0.01 for IL-18, and 12.79 pg/mL, IQR 6.56 to 19.34pg/mL, P <0.001 and P <0.05 for IFN-α). However, there were no significant differences between AOSD or SLE patients and healthy controls in serum levels of TNF-α.


Involvement of TLR7 MyD88-dependent signaling pathway in the pathogenesis of adult-onset Still's disease.

Chen DY, Lin CC, Chen YM, Lan JL, Hung WT, Chen HH, Lai KL, Hsieh CW - Arthritis Res. Ther. (2013)

Serum cytokines levels and the fold-increases of supernatant cytokines levels after stimulation with the Toll-like receptor (TLR)7 ligand. The comparison in serum levels of cytokines, including IL-1β (A), IL-6 (B), IL-18 (C), TNF-α (D), and IFN-α (E) among patients with adult-onset Still's disease (AOSD), patients with systemic lupus erythematosus (SLE), and healthy controls (HCs). To explore the functional role of TLR7, we examined the fold-increases of supernatant cytokines levels, including IL-1β (F), IL-6 (G), IL-18 (H), TNF-α (I), and IFN-α (J) after stimulation with the TLR7 ligand (imiquimod 5 μg/mL) in AOSD patients, SLE patients, and HCs. The horizontal line indicates the median value for each group. The P-value was determined by the Mann-Whitney U-test.
© Copyright Policy - open-access
Related In: Results  -  Collection

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Show All Figures
getmorefigures.php?uid=PMC3672755&req=5

Figure 3: Serum cytokines levels and the fold-increases of supernatant cytokines levels after stimulation with the Toll-like receptor (TLR)7 ligand. The comparison in serum levels of cytokines, including IL-1β (A), IL-6 (B), IL-18 (C), TNF-α (D), and IFN-α (E) among patients with adult-onset Still's disease (AOSD), patients with systemic lupus erythematosus (SLE), and healthy controls (HCs). To explore the functional role of TLR7, we examined the fold-increases of supernatant cytokines levels, including IL-1β (F), IL-6 (G), IL-18 (H), TNF-α (I), and IFN-α (J) after stimulation with the TLR7 ligand (imiquimod 5 μg/mL) in AOSD patients, SLE patients, and HCs. The horizontal line indicates the median value for each group. The P-value was determined by the Mann-Whitney U-test.
Mentions: As shown in Figure 3A-E, significantly higher median levels of serum IL-1β, IL-6, IL-18, and IFN-α in patients with active AOSD (19.65 pg/mL, IQR 3.55 to 32.79 pg/mL, 984.98 pg/mL, IQR 409.24 to 2064.92 pg/mL, 2,613.44 pg/mL, IQR 983.04 to 5,765.09 pg/ml, and 45.02 pg/mL, IQR 26.27 to 91.26 pg/mL, respectively) and higher median levels of serum IL-6, IL-18, and IFN-α in active SLE patients (405.48 pg/mL, IQR 330.32 to 945.83 pg/mL; 605.10 pg/mL, IQR 539.52 to 708.98 pg/mL, and 43.21 pg/mL, IQR 16.23 to 49.12 pg/mL, respectively) were observed when compared to those in healthy controls (2.61 pg/mL, IQR 2.49 to 5.22 pg/mL, P <0.05 for IL-1β; 85.78 pg/mL, IQR 33.38 to 249.22 pg/mL, P <0.001 and P <0.005 for IL-6; 322.69 pg/mL, IQR 222.50 to 424.03pg/mL, P <0.001 and P <0.01 for IL-18, and 12.79 pg/mL, IQR 6.56 to 19.34pg/mL, P <0.001 and P <0.05 for IFN-α). However, there were no significant differences between AOSD or SLE patients and healthy controls in serum levels of TNF-α.

Bottom Line: Significantly higher median frequencies of TLR7-expressing pre-mDCs and mDCs were observed in AOSD patients (65.5% and 14.9%, respectively) and in SLE patients (60.3% and 14.4%, respectively) than in HC (42.8% and 8.8%, respectively; both P <0.001).TLR7 ligand (imiquimod) stimulation of PBMCs resulted in significantly enhanced levels of interleukin (IL)-1β, IL-6, IL-18 and IFN-α in AOSD and SLE patients.The overexpression of TLR7 MyD88-dependent signaling molecules may be a common pathogenic mechanism for both AOSD and SLE.

View Article: PubMed Central - HTML - PubMed

ABSTRACT

Introduction: The objective of this study was to investigate the potential role of the Toll-like receptor 7 (TLR7) signaling pathway in the pathogenesis of adult-onset Still's disease (AOSD).

Methods: Frequencies of TLR7-expressing precursor of myeloid dendritic cells (pre-mDCs) and mDCs in 28 AOSD patients, 28 patients with systemic lupus erythematosus (SLE) and 12 healthy controls (HC) were determined by flow cytometry analysis. Transcript and protein levels of TLR7 signaling molecules in peripheral blood mononuclear cells (PBMCs) were evaluated by quantitative PCR and western blotting respectively. Serum cytokines levels were measured by ELISA.

Results: Significantly higher median frequencies of TLR7-expressing pre-mDCs and mDCs were observed in AOSD patients (65.5% and 14.9%, respectively) and in SLE patients (60.3% and 14.4%, respectively) than in HC (42.8% and 8.8%, respectively; both P <0.001). Transcript and protein levels of TLR7-signaling molecules, including MyD88, TRAF6, IRAK4 and IFN-α, were upregulated in AOSD patients and SLE patients compared with those in HC. Disease activity scores were positively correlated with the frequencies of TLR7-expressing mDCs and expression levels of TLR7 signaling molecules in both AOSD and SLE patients. TLR7 ligand (imiquimod) stimulation of PBMCs resulted in significantly enhanced levels of interleukin (IL)-1β, IL-6, IL-18 and IFN-α in AOSD and SLE patients. Frequencies of TLR7-expressing mDCs and expression levels of TLR7 signaling molecules significantly decreased after effective therapy.

Conclusions: Elevated levels of TLR7 signaling molecules and their positive correlation with disease activity in AOSD patients suggest involvement of the TLR7 signaling pathway in the pathogenesis of this disease. The overexpression of TLR7 MyD88-dependent signaling molecules may be a common pathogenic mechanism for both AOSD and SLE.

Show MeSH
Related in: MedlinePlus