Hong Ping Zhang1,2, Lei Wang2, Juan Juan Fu2, Tao Fan2, Zeng Li Wang3, Gang Wang1,2. 1. Pneumology Group, Department of Integrated Traditional Chinese and Western Medicine, State Key Laboratory of Biotherapy of China, West China Hospital, Sichuan University, Chengdu, China. 2. Pneumology Group, Department of Integrated Traditional Chinese and Western Medicine, West China Hospital, Sichuan University, Chengdu, China. 3. Department of Respiratory and Critical Care Medicine, West China Hospital, Sichuan University, Chengdu, China.
Abstract
BACKGROUND AND OBJECTIVE: T lymphocytes, which are characterized by longevity and immune memory, play an important role in airway inflammation in asthma. Here, we assessed the association between immune memory and histone deacetylation and/or acetylation status. METHODS: CD4 + CD45RB(low) cells (memory T (Tm)) obtained from the spleens of asthma mice models were co-cultured with glucocorticoids (GCs), trichostatin A (TSA) or anacardic acid (AA) and adoptively transferred to naïve mice. Interleukin (IL)-4, 5 and 13 and IFN-γ concentrations were measured in culture supernatants and bronchoalveolar lavage fluid (BALF). Histone deacetylase (HDAC) and histone acetyltransferase (HAT) activities and the expression of T-bet, GATA-3, HDACs 1-11 and alveolar eosinophilic inflammation index (AEII) were determined in lung tissues. RESULTS: Culture supernatants and the BALF showed similar cytokine profiles. AA and GCs significantly inhibited HAT activity (P = 0.002 and P = 0.018), whereas TSA inhibited and GCs promoted HDAC activity (P = 0.004 and P = 0.025). HDACs 7, 9 and 10 were upregulated by AA and GCs (all P < 0.032), while HDAC11 was upregulated by GCs (P = 0.028). GC-induced inhibition of Tm histone acetylation alleviated AEII by downregulating IL-4, 5 and 13, similar to the effect of AA. CONCLUSION: Histone hyperacetylation status induced by low expression of HDACs 7, 9 and 10 in allergen-specific Tm cells contributes to eosinophilic airway inflammation. The mechanism by which GCs improve airway inflammation involves the upregulation of HDACs 7, 9, 10 and 11 and especially HDAC-10. The role of individual HDACs and AA as novel therapeutic agents for allergic asthma needs to be explored in the future.
BACKGROUND AND OBJECTIVE: T lymphocytes, which are characterized by longevity and immune memory, play an important role in airway inflammation in asthma. Here, we assessed the association between immune memory and histone deacetylation and/or acetylation status. METHODS:CD4 + CD45RB(low) cells (memory T (Tm)) obtained from the spleens of asthmamice models were co-cultured with glucocorticoids (GCs), trichostatin A (TSA) or anacardic acid (AA) and adoptively transferred to naïve mice. Interleukin (IL)-4, 5 and 13 and IFN-γ concentrations were measured in culture supernatants and bronchoalveolar lavage fluid (BALF). Histone deacetylase (HDAC) and histone acetyltransferase (HAT) activities and the expression of T-bet, GATA-3, HDACs 1-11 and alveolar eosinophilic inflammation index (AEII) were determined in lung tissues. RESULTS: Culture supernatants and the BALF showed similar cytokine profiles. AA and GCs significantly inhibited HAT activity (P = 0.002 and P = 0.018), whereas TSA inhibited and GCs promoted HDAC activity (P = 0.004 and P = 0.025). HDACs 7, 9 and 10 were upregulated by AA and GCs (all P < 0.032), while HDAC11 was upregulated by GCs (P = 0.028). GC-induced inhibition of Tm histone acetylation alleviated AEII by downregulating IL-4, 5 and 13, similar to the effect of AA. CONCLUSION: Histone hyperacetylation status induced by low expression of HDACs 7, 9 and 10 in allergen-specific Tm cells contributes to eosinophilic airway inflammation. The mechanism by which GCs improve airway inflammation involves the upregulation of HDACs 7, 9, 10 and 11 and especially HDAC-10. The role of individual HDACs and AA as novel therapeutic agents for allergic asthma needs to be explored in the future.