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Abstract Number: 1613

Anti-Malarial Drugs (hydroxychloroquine and quinacrine) Decrease The Production Of Interferon-Alfa Initiated By TLR-9 Agonist

Ou Jin1, Xi Zhang1, Qiuxia Li1, Lingkai Fang1, Hongyue Huang1, Chengcheng Hou1, Zetao Liao1, Qiujing Wei1, Zhiming Lin2, Dongfang Lin1 and Jieruo Gu3, 1Rheumatology, The Affiliated Third Hospital of Sun Yat-san University, Rheumatology, Guangzhou, China, 2Rheumatology, third affiliated hospital of Sun Yat-sen Universtiy, Guangzhou, China, 3Medicine, Third Affiliated Hospital of Sun Yat-sen University, GuangZhou, China

Meeting: 2013 ACR/ARHP Annual Meeting

Keywords: Antimalarial drugs, interferons, systemic lupus erythematosus (SLE) and toll-like receptors

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Session Information

Session Title: Systemic Lupus Erythematosus - Clinical Aspects II: Central Nervous System Manifestations, Therapeutics

Session Type: Abstract Submissions (ACR)

Background/Purpose:

Toll-like receptor 9 (TLR-9) plays an important role in initiating innate immunity.  The recognition of self DNA fragments by TLR-9 may results in the production of interferon-α, a central cytokine in the pathogenesis of Systemic lupus erythematosus (SLE). Anti-malarial drugs such as hydroxychloroquine (HCQ) and quinacrine (Qn) are commonly used in the treatment of SLE. Some studies imply that anti-malarial drugs may influence TLR pathway, though detail mechanisms are still under study. In this study, we want to evaluate the influence of anti-malarial drugs (HCQ and Qn) on the initiation of IFN-α production through TLR-9 pathway, combinded with or without glucocorticoid.

Methods:

Freshly isolated PBMCs of healthy donors were stimulated with the TLR-9 agonist CpG oligodeoxynucleotides (CpG-A ODN)-2216, then incubated with different kinds of anti-malarial drugs ( HCQ and Qn or both) and / or different doses of glucocorticoid (hydrocortisone: 10-6M (low dose), 10-5M (median dose), 10-4M (high dose), 10-3M (pulse dose)). The changes in the expression of IFN-α were detected by real time PCR.

Results:

 (1). Hydroxychloroquine or quinacrine alone or combined together significantly inhibited the production of IFN-α initiated by ODN 2216 (Qn (p=0.047), HCQ (p=0.047), Qn and HCQ (p=0.046)). (2). When combined with low (10-6M), median (10-5M), or high (10-4M) dose of hydrocortisone, HCQ or Qn or both significantly revised the elevation of IFN-α caused by ODN 2216 ((low dose: Qn (p=0.017), HCQ (p=0.017), Qn & HCQ (p=0.017), median dose: Qn (p=0.034), HCQ (p=0.032), Qn & HCQ (p=0.036), high dose: Qn (p=0.028), HCQ (p=0.024), Qn & HCQ (p=0.028)), which cannot be decreased by glucocorticoid (each p>0.05). (3). When combined with pulse dose (10-3M) hydrocortisone which could promote the expression of IFN-α to some extent, anti-malarial drugs (HCQ, Qn alone or both) could not significantly down-regulate the expression of IFN-α stimulated by ODN 2216.

Conclusion:

(1). Anti-malarial drugs hamper the production of IFN-α by TLR-9 recognition of nucleotides (ODN 2216), which is the critical cytokine in the pathogenesis of lupus. (2). The combination with anti-malarial drugs (HCQ, Qn alone or both) seem to be a good choice to help low, median, high dose glucocorticoid to achieve a better disease control by inhibiting IFN-α, which cannot be decreased by glucocorticoid. (3). When combined with pulse dose glucocorticoid, anti-malarial drugs (HCQ, Qn alone or both) could not down-regulate the expression of IFN-α stimulated by TLR-9 agonist.


Disclosure:

O. Jin,
None;

X. Zhang,
None;

Q. Li,
None;

L. Fang,
None;

H. Huang,
None;

C. Hou,
None;

Z. Liao,
None;

Q. Wei,
None;

Z. Lin,
None;

D. Lin,
None;

J. Gu,
None.

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