BF02, a recombinant TNFR2 fusion protein, alleviates adjuvant arthritis by regulating T lymphocytes in rats
Abstract
Shan-shan SONG, Bei HUANG, Qing-tong WANG, Yu-jing WU, Jing-jing FU, Yun-fang ZHANG, Yan CHANG, Jing-yu CHEN, Hua-xun WU, Di WANG, Ling-ling ZHANG*, Wei WEI*
Institute of Clinical Pharmacology, Anhui Medical University, Key Laboratory of Anti-inflammatory and Immunopharmacology of Education Ministry of China, Hefei 230032, China
Aim: To investigate the therapeutic effects of BF02 on adjuvant arthritis (AA) in rats and the regulatory effects of BF02 on T lymphocyte function.
Methods: SD rats received a single intradermal injection of Freund’s complete adjuvant emulsion into the right hind metatarsal footpad. After the onset of AA, the rats were injected BF02 (1, 3, or 9 mg/kg, sc) every 3 d for a total of 15 d. Intragastric administration of methotrexate (MTX, 0.5 mg/kg, every 3 d for a total of 15 d) was taken as the positive control drug. Arthritis index, swollen joint count, ankle joint histopathology, spleen histopathology and the paw radiography were used for evaluating the drug effects on AA rats. T lymphocyte function was assessed by measuring T lymphocyte cytokine levels, IL17 and TNF-α mRNA expression levels, and percentage of T lymphocyte subsets.
Results: In the AA rats, remarkable secondary inflammatory responses exhibited, accompanied by significantly higher levels of IL-1, IL-6, TNF-α, IL-17, LTα, RANKL, and MMP-13. The expression of IL17 and TNF-α mRNAs was also substantially higher than in normal rats. The percentages of CD3+CD4+ and CD4+CD25+ T lymphocytes were increased, whereas the percentages of CD4+CD62L+ and CD4+CD25+FoxP3+ T lymphocytes were decreased. Treatment of the AA rats with BF02 (9 mg/kg) or MTX significantly decreased the arthritis index, swollen joint count and arthritis global assessment. Moreover, both BF02 (9 mg/kg) and MTX significantly inhibited T lymphocyte proliferation, and blocked the above mentioned aberrance in T lymphocyte cytokine levels, IL17 and TNF-α mRNA expression, and percentages of T lymphocyte subsets.
Conclusion: BF02 exerts therapeutic effects on AA rats via the regulation of T lymphocytes.
Keywords: adjuvant arthritis; inflammation; TNF-α; BF02; methotrexate; T lymphocytes; cytokine
This work was supported by the National Natural Science Foundation of China (No 30973543, 31100640, and 81173075) and the Anhui Province Natural Science Foundation (No 11040606M195).
* To whom correspondence should be addressed.
E-mail llzhang@ahmu.edu.cn (Ling-ling ZHANG); wwei@ahmu.edu.cn (Wei WEI)
Received 2012-08-08 Accepted 2012-11-16
Keywords:
Institute of Clinical Pharmacology, Anhui Medical University, Key Laboratory of Anti-inflammatory and Immunopharmacology of Education Ministry of China, Hefei 230032, China
Aim: To investigate the therapeutic effects of BF02 on adjuvant arthritis (AA) in rats and the regulatory effects of BF02 on T lymphocyte function.
Methods: SD rats received a single intradermal injection of Freund’s complete adjuvant emulsion into the right hind metatarsal footpad. After the onset of AA, the rats were injected BF02 (1, 3, or 9 mg/kg, sc) every 3 d for a total of 15 d. Intragastric administration of methotrexate (MTX, 0.5 mg/kg, every 3 d for a total of 15 d) was taken as the positive control drug. Arthritis index, swollen joint count, ankle joint histopathology, spleen histopathology and the paw radiography were used for evaluating the drug effects on AA rats. T lymphocyte function was assessed by measuring T lymphocyte cytokine levels, IL17 and TNF-α mRNA expression levels, and percentage of T lymphocyte subsets.
Results: In the AA rats, remarkable secondary inflammatory responses exhibited, accompanied by significantly higher levels of IL-1, IL-6, TNF-α, IL-17, LTα, RANKL, and MMP-13. The expression of IL17 and TNF-α mRNAs was also substantially higher than in normal rats. The percentages of CD3+CD4+ and CD4+CD25+ T lymphocytes were increased, whereas the percentages of CD4+CD62L+ and CD4+CD25+FoxP3+ T lymphocytes were decreased. Treatment of the AA rats with BF02 (9 mg/kg) or MTX significantly decreased the arthritis index, swollen joint count and arthritis global assessment. Moreover, both BF02 (9 mg/kg) and MTX significantly inhibited T lymphocyte proliferation, and blocked the above mentioned aberrance in T lymphocyte cytokine levels, IL17 and TNF-α mRNA expression, and percentages of T lymphocyte subsets.
Conclusion: BF02 exerts therapeutic effects on AA rats via the regulation of T lymphocytes.
Keywords: adjuvant arthritis; inflammation; TNF-α; BF02; methotrexate; T lymphocytes; cytokine
This work was supported by the National Natural Science Foundation of China (No 30973543, 31100640, and 81173075) and the Anhui Province Natural Science Foundation (No 11040606M195).
* To whom correspondence should be addressed.
E-mail llzhang@ahmu.edu.cn (Ling-ling ZHANG); wwei@ahmu.edu.cn (Wei WEI)
Received 2012-08-08 Accepted 2012-11-16