Interferon-β inhibits toll-like receptor 9 processing in multiple sclerosis.
OBJECTIVE
Viral infections have been implicated in the pathogenesis of multiple sclerosis (MS). Plasmacytoid dendritic cells (pDCs) are present in peripheral blood, cerebrospinal fluid, and brain lesions of MS patients. pDCs sense viral DNA via Toll-like receptor 9 (TLR9), which has to be cleaved from the N-terminal to become functional (TLR9 processing). pDCs activated with TLR9 agonists promote T-helper type 1 (Th1)/T-helper type 17 (Th17) responses. In the animal model of MS, TLR9 agonists can induce disease. We hypothesized that pDCs are inhibited by disease-modifying therapy such as interferon (IFN)-β, consequently decreasing the frequency of MS attacks.


METHODS
We separated pDCs from healthy subjects and patients diagnosed with relapsing-remitting MS and clinically isolated syndrome. Cytokine secretion by pDCs activated with TLR9 agonists was measured by enzyme-linked immunosorbent assay and multianalyte profiling. TLR9 gene and protein expression was studied by DNA microarrays and western blot.


RESULTS
In untreated patients, pDCs activated with TLR9 agonists produced increased levels of IFN-α, a Th1-promoting cytokine, as compared to healthy subjects. In IFN-β-treated patients, activated pDCs had decreased ability to produce both IFN-α and the proinflammatory cytokines interleukin (IL)-6 and tumor necrosis factor α as compared to untreated patients. pDCs separated from IFN-β-treated patients had significantly reduced levels of the processed TLR9 protein but normal levels of the full-length TLR9 protein and TLR9 gene expression as compared to untreated patients.


CONCLUSIONS
This finding represents a novel immunomodulatory mechanism of IFN-β: inhibition of TLR9 processing. This results in decreased activation of pDCs by viral pathogens and, thus, may affect the frequency of MS exacerbations.
Department of Neurology, University of Medicine and Dentistry, New Jersey-Robert Wood Johnson Medical School, New Brunswick, NJ 08901, USA. kbalashov@yahoo.com
Konstantin E
KE
Balashov
Latt Latt
LL
Aung
Adi
A
Vaknin-Dembinsky
Suhayl
S
Dhib-Jalbut
Howard L
HL
Weiner
D000293:Adolescent; D000328:Adult; D002478:Cells, Cultured; D003713:Dendritic Cells / Q000187:drug effects* / Q000821:virology; D004797:Enzyme-Linked Immunosorbent Assay / Q000379:methods; D005260:Female; D020869:Gene Expression Profiling / Q000379:methods; D005786:Gene Expression Regulation / Q000187:drug effects*; D006801:Humans; D007155:Immunologic Factors / Q000494:pharmacology*; D050839:Interferon Regulatory Factor-7 / Q000235:genetics / Q000378:metabolism; D016899:Interferon-beta / Q000378:metabolism / Q000494:pharmacology* / Q000627:therapeutic use; D015850:Interleukin-6 / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D009103:Multiple Sclerosis / Q000097:blood* / Q000188:drug therapy; D020411:Oligonucleotide Array Sequence Analysis / Q000379:methods; D051217:Toll-Like Receptor 9 / Q000819:agonists / Q000235:genetics / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D055815:Young Adult
C494234:IRF7 protein, human; D007155:Immunologic Factors; D050839:Interferon Regulatory Factor-7; D015850:Interleukin-6; C495371:TLR9 protein, human; D051217:Toll-Like Receptor 9; D014409:Tumor Necrosis Factor-alpha; D016899:Interferon-beta