Publication: Role of autophagy in regulating interleukin-10 and the responses to corticosteroids and statins in asthma
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Issued Date
2021-12-01
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ISSN
13652222
09547894
09547894
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2-s2.0-85099936538
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Mahidol University
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SCOPUS
Bibliographic Citation
Clinical and Experimental Allergy. Vol.51, No.12 (2021), 1553-1565
Suggested Citation
Kittipong Maneechotesuwan, Kanda Kasetsinsombat, Adisak Wongkajornsilp, Peter J. Barnes Role of autophagy in regulating interleukin-10 and the responses to corticosteroids and statins in asthma. Clinical and Experimental Allergy. Vol.51, No.12 (2021), 1553-1565. doi:10.1111/cea.13825 Retrieved from: https://repository.li.mahidol.ac.th/handle/123456789/77188
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Title
Role of autophagy in regulating interleukin-10 and the responses to corticosteroids and statins in asthma
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Abstract
Background: Interleukin (IL)-10 is a key anti-inflammatory cytokine that may be reduced in asthma but is enhanced by corticosteroids, especially when combined with a statin, although the mechanisms of these effects are uncertain. Objective: To study the role of autophagy in macrophages in promoting inflammation in asthma through reducing IL-10 secretion and how corticosteroids and statins may reverse this process. Methods: We conducted a randomised double-blind placebo-controlled study in moderate to severe asthmatic patients (n = 44) to investigate the effect of an inhaled corticosteroid (budesonide 400 μg/day) and the combination of budesonide with an oral statin (simvastatin 10 mg/day) given for 8 weeks on autophagy protein expression in sputum cells by using immunocytochemistry and measurement of IL-10 release. In in vitro experiments, we studied cross-regulation between autophagy and IL-10 release by measuring the expression of autophagy proteins in M2-like macrophages and the effects of budesonide and simvastatin on these mechanisms. Results: In asthmatic patients, inhaled budesonide inhibited airway macrophage autophagy (beclin-1, LC3) as well as autophagic flux (p62), which was enhanced by simvastatin and was correlated with increased sputum IL-10 and reduced IL-4 concentrations. In macrophages in vitro, budesonide and simvastatin inhibited rapamycin-induced autophagy as well as autophagic flux, with reduced expression of beclin-1 and LC3, but enhanced the accumulation of p62 and increased expression of IL-10, which itself further inhibited autophagy in macrophages. With siRNA-mediated silencing, LC3-deficient macrophages also showed a maximal induction of IL-10 transcription. Neutralisation of IL-10 with recombinant specific blocking antibody and silencing IL-10 transcription reversed the inhibitory effects of budesonide and simvastatin on macrophage autophagy. Conclusion and clinical relevance: Inhibition by corticosteroids and a statin of macrophage autophagy enhances IL-10 production, resulting in the control of asthmatic inflammation.