Dataset Information

Hydroxychloroquine is associated with impaired interferon-alpha and tumor necrosis factor-alpha production by plasmacytoid dendritic cells in systemic lupus erythematosus.

ABSTRACT:

Introduction

Plasmacytoid dendritic cells (pDCs) constitutively express two members of the Toll-like receptor (TLR) family, TLR-9 and TLR-7, through which they can be stimulated to produce high levels of interferon (IFN)-?, a key mediator of the pathogenesis of systemic lupus erythematosus (SLE). Given the known efficacy of hydroxychloroquine (HCQ) in the treatment of SLE, we examined its ability to inhibit such pDC function in vivo.

Methods

Peripheral blood mononuclear cells (PBMCs) from SLE subjects treated or not with HCQ and from healthy controls were stimulated with the TLR-9 agonist, CpG oligodeoxynucleotides (CpG-A ODN)-2216, and the TLR-7 agonist, imiquimod. The proportion of monocytes, B cells, myeloid dendritic cells, pDCs, and natural killer (NK) cells producing IFN-? and tumor necrosis factor alpha (TNF-?) was then analyzed by multiparameter flow cytometry.

Results

After TLR-9/7 stimulation in both SLE and healthy subjects, significant production of IFN-? and TNF-? was only observed in pDCs. TLR-7 and TLR-9 induced IFN-? and TNF-? production by pDCs from subjects with SLE was decreased relative to that found in controls (TLR-9/IFN-?, P < 0.0001; TLR-9/TNF-? P < 0.0001; TLR-7/TNF-? P = 0.01). TLR-9 and TLR-7 induced IFN-? and TNF-? production by pDCs was severely impaired in 36% (TLR-9) and 33% (TLR-7) of SLE subjects. In almost all cases, these subjects were being treated with HCQ (HCQ vs. no HCQ: impaired TLR-9/IFN-?, P = 0.0003; impaired TLR-7/IFN-?, P = 0.07; impaired TLR-9/TNF-?, P < 0.009; impaired TLR-7/TNF-?, P < 0.01).

Conclusions

Treatment with HCQ is associated with impaired ability of pDCs from subjects with SLE to produce IFN-? and TNF-? upon stimulation with TLR-9 and TLR-7 agonists.

SUBMITTER: Sacre K

PROVIDER: S-EPMC3446541 | biostudies-literature | 2012 Jun

REPOSITORIES: biostudies-literature

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Publications

Hydroxychloroquine is associated with impaired interferon-alpha and tumor necrosis factor-alpha production by plasmacytoid dendritic cells in systemic lupus erythematosus.

Sacre Karim K Criswell Lindsey A LA McCune Joseph M JM

Arthritis research & therapy 20120627 3

<h4>Introduction</h4>Plasmacytoid dendritic cells (pDCs) constitutively express two members of the Toll-like receptor (TLR) family, TLR-9 and TLR-7, through which they can be stimulated to produce high levels of interferon (IFN)-α, a key mediator of the pathogenesis of systemic lupus erythematosus (SLE). Given the known efficacy of hydroxychloroquine (HCQ) in the treatment of SLE, we examined its ability to inhibit such pDC function in vivo.<h4>Methods</h4>Peripheral blood mononuclear cells (PBM ...[more]

PMID: 22734582

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Project description:BackgroundIt is well known that interferon (IFN)-alpha is important to the pathogenesis of systemic lupus erythematosus (SLE). However, several reports have indicated that the number of IFN-alpha producing cells are decreased or that their function is defective in patients with SLE. We studied the function of plasmacytoid dendritic cells (pDCs) under persistent stimulation of Toll-like receptor (TLR)9 via a TLR9 ligand (CpG ODN2216) or SLE serum.MethodsThe concentrations of IFN-alpha were determined in serum and culture supernatant of peripheral blood mononuclear cells (PBMCs) from SLE patients and healthy controls after stimulation with CpG ODN2216 or SLE serum. The numbers of circulating pDCs were analyzed by fluoresence-activated cell sorting analysis. pDCs were treated with CpG ODN2216 and SLE serum repeatedly, and levels of produced IFN-alpha were measured. The expression of IFN-alpha signature genes and inhibitory molecules of TLR signaling were examined in PBMCs from SLE patients and healthy control individuals.ResultsAlthough there was no significant difference in serum concentration of IFN-alpha and number of circulating pDCs between SLE patients and healthy control individuals, the IFN-alpha producing capacity of PBMCs was significantly reduced in SLE patients. Interestingly, the degree which TLR9 ligand-induced IFN-alpha production in SLE PBMCs was inversely correlated with the SLE serum-induced production of IFN-alpha in healthy PMBCs. Because repeated stimulation pDCs with TLR9 ligands showed decreased level of IFN-alpha production, continuous TLR9 stimulation may lead to decreased production of IFN-alpha in SLE PBMCs. In addition, PBMCs isolated from SLE patients exhibited higher expression of IFN-alpha signature genes and inhibitory molecules of TLR signaling, indicating that these cells had already undergone IFN-alpha stimulation and had become desensitized to TLR signaling.ConclusionWe suggest that the persistent presence of endogenous IFN-alpha inducing factors induces TLR tolerance in pDCs of SLE patients, leading to impaired production of IFN-alpha.

Dataset Information

Hydroxychloroquine is associated with impaired interferon-alpha and tumor necrosis factor-alpha production by plasmacytoid dendritic cells in systemic lupus erythematosus.

Introduction

Methods

Results

Conclusions

Publications

Hydroxychloroquine is associated with impaired interferon-alpha and tumor necrosis factor-alpha production by plasmacytoid dendritic cells in systemic lupus erythematosus.

Similar Datasets

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