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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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Transcript and protein levels of Toll-like receptor (TLR)7 signaling molecules in patients with adult-onset Still's disease (AOSD), patients with systemic lupus erythematosus (SLE), and healthy volunteers. The comparison in transcript levels of TLR7 signaling molecules, including TLR7 (A), Myeloid differentiation primary-response protein 88 (MyD88) (B), IL-1 receptor-associated kinase (IRAK)4 (C), TNF receptor-associated factor (TRAF)6 (D), IFN regulatory factor (IRF)5 (E), and IFN-α (F) among AOSD patients, SLE patients, and healthy controls (HCs). The horizontal line indicates median value for each group. Immunoblot analyses (G) for protein expression of TLR7 signaling molecules in the lysates of peripheral blood samples from six AOSD patients, three SLE patients and three healthy volunteers. The comparison in the protein expression levels of TLR7 signaling molecules among three groups (H). Bars show the mean ± standard error of the mean; *P <0.05 versus healthy controls (Mann-Whitney U-test).
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Figure 2: Transcript and protein levels of Toll-like receptor (TLR)7 signaling molecules in patients with adult-onset Still's disease (AOSD), patients with systemic lupus erythematosus (SLE), and healthy volunteers. The comparison in transcript levels of TLR7 signaling molecules, including TLR7 (A), Myeloid differentiation primary-response protein 88 (MyD88) (B), IL-1 receptor-associated kinase (IRAK)4 (C), TNF receptor-associated factor (TRAF)6 (D), IFN regulatory factor (IRF)5 (E), and IFN-α (F) among AOSD patients, SLE patients, and healthy controls (HCs). The horizontal line indicates median value for each group. Immunoblot analyses (G) for protein expression of TLR7 signaling molecules in the lysates of peripheral blood samples from six AOSD patients, three SLE patients and three healthy volunteers. The comparison in the protein expression levels of TLR7 signaling molecules among three groups (H). Bars show the mean ± standard error of the mean; *P <0.05 versus healthy controls (Mann-Whitney U-test).

Mentions: As shown in Figure 2, significantly higher transcript levels of TLR7, MyD88, IRAK4, TRAF6, and IFN-α were observed in active AOSD patients (median 145.64, IQR 7.07 to 814.81; 2.08, IQR 1.53 to 8.55; 4.55, IQR 1.55 to 14.49; 13.86, IQR 4.80 to 45.04; 46.23, IQR 15.51 to 154.05, respectively) than those in healthy controls (0.48, IQR 0.23 to 8.62; 1.12, IQR 0.79 to 1.40; 0.59, IQR 0.51 to 2.62; 0.55, IQR 0.40 to 3.80; 0.61, IQR 0.10 to 11.30, respectively (all P <0.001). Significantly higher transcript levels of TLR7, MyD88, and IFN-α were also observed in active SLE patients (median 43.47, IQR 9.30 to 103.07; 2.08, IQR 0.85 to 4.87; 24.91, IQR 6.20 to 188.90, respectively) than those in healthy controls (P <0.001, P <0.05, P <0.001, respectively). No significant differences were observed between AOSD or SLE patients and healthy controls in the transcript levels of IRF-5.


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)

Transcript and protein levels of Toll-like receptor (TLR)7 signaling molecules in patients with adult-onset Still's disease (AOSD), patients with systemic lupus erythematosus (SLE), and healthy volunteers. The comparison in transcript levels of TLR7 signaling molecules, including TLR7 (A), Myeloid differentiation primary-response protein 88 (MyD88) (B), IL-1 receptor-associated kinase (IRAK)4 (C), TNF receptor-associated factor (TRAF)6 (D), IFN regulatory factor (IRF)5 (E), and IFN-α (F) among AOSD patients, SLE patients, and healthy controls (HCs). The horizontal line indicates median value for each group. Immunoblot analyses (G) for protein expression of TLR7 signaling molecules in the lysates of peripheral blood samples from six AOSD patients, three SLE patients and three healthy volunteers. The comparison in the protein expression levels of TLR7 signaling molecules among three groups (H). Bars show the mean ± standard error of the mean; *P <0.05 versus healthy controls (Mann-Whitney U-test).
© Copyright Policy - open-access
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Figure 2: Transcript and protein levels of Toll-like receptor (TLR)7 signaling molecules in patients with adult-onset Still's disease (AOSD), patients with systemic lupus erythematosus (SLE), and healthy volunteers. The comparison in transcript levels of TLR7 signaling molecules, including TLR7 (A), Myeloid differentiation primary-response protein 88 (MyD88) (B), IL-1 receptor-associated kinase (IRAK)4 (C), TNF receptor-associated factor (TRAF)6 (D), IFN regulatory factor (IRF)5 (E), and IFN-α (F) among AOSD patients, SLE patients, and healthy controls (HCs). The horizontal line indicates median value for each group. Immunoblot analyses (G) for protein expression of TLR7 signaling molecules in the lysates of peripheral blood samples from six AOSD patients, three SLE patients and three healthy volunteers. The comparison in the protein expression levels of TLR7 signaling molecules among three groups (H). Bars show the mean ± standard error of the mean; *P <0.05 versus healthy controls (Mann-Whitney U-test).
Mentions: As shown in Figure 2, significantly higher transcript levels of TLR7, MyD88, IRAK4, TRAF6, and IFN-α were observed in active AOSD patients (median 145.64, IQR 7.07 to 814.81; 2.08, IQR 1.53 to 8.55; 4.55, IQR 1.55 to 14.49; 13.86, IQR 4.80 to 45.04; 46.23, IQR 15.51 to 154.05, respectively) than those in healthy controls (0.48, IQR 0.23 to 8.62; 1.12, IQR 0.79 to 1.40; 0.59, IQR 0.51 to 2.62; 0.55, IQR 0.40 to 3.80; 0.61, IQR 0.10 to 11.30, respectively (all P <0.001). Significantly higher transcript levels of TLR7, MyD88, and IFN-α were also observed in active SLE patients (median 43.47, IQR 9.30 to 103.07; 2.08, IQR 0.85 to 4.87; 24.91, IQR 6.20 to 188.90, respectively) than those in healthy controls (P <0.001, P <0.05, P <0.001, respectively). No significant differences were observed between AOSD or SLE patients and healthy controls in the transcript levels of IRF-5.

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