Anti-inflammatory effects of budesonide in human lung fibroblasts are independent of histone deacetylase 2

Xingqi Wang, Amy Nelson, Zachary M. Weiler, Amol N Patil, Tadashi Sato, Nobuhiro Kanaji, Masanori Nakanishi, Joel Michalski, Maha Farid, Hesham E Basma, Tricia D LeVan, Anna Miller-Larsson, Elisabet Wieslander, Kai Christian Muller, Olaf Holz, Helgo Magnussen, Klaus F. Rabe, Xiang-de Liu, Stephen I. Rennard

Research output: Contribution to journalArticle

6 Citations (Scopus)

Abstract

Objective and design: Reduced expression of histone deacetylase 2 (HDAC2) in alveolar macrophages and epithelial cells may account for reduced response of chronic obstructive pulmonary disease (COPD) patients to glucocorticoids. HDAC2 expression and its role in mediating glucocorticoid effects on fibroblast functions, however, has not been fully studied. This study was designed to investigate whether HDAC2 mediates glucocorticoid effects on release of inflammatory cytokines and matrix metalloproteinases (MMPs) from human lung fibroblasts. Methods: Human lung fibroblasts (HFL-1 cells) were stimulated with interleukin (IL)-1β plus tumor necrosis factor (TNF)-α in the presence or absence of the glucocorticoid budesonide. Cytokines (IL-6 and IL-8) were quantified by enzyme linked immunosorbent assay (ELISA) and MMPs (MMP-1 and MMP-3) by immunoblotting in culture medium. The role of HDAC2 was investigated using a pharmacologic inhibitor as well as a small interfering ribonucleic acid (siRNA) targeting HDAC2. Results: We have demonstrated that budesonide concentration-dependently (10-10-10-7 M) inhibited IL-6, IL-8, MMP-1, and MMP-3 release by HFL-1 cells in response to IL-1β plus TNF-a. While an HDAC inhibitor significantly blocked the inhibitory effect of budesonide on human bronchial epithelial cells (HBECs) and monocytes (THP-1 cells), it did not block the inhibitory effect of budesonide on release of cytokines and MMPs from HFL-1 cells. Similarly, an HDAC2-siRNA blocked budesonide inhibition of cytokine release in HBECs, but it did not block the inhibitory effect of budesonide on HFL-1 cytokine and MMP release. Furthermore, budesonide significantly blocked release of cytokines and MMPs to a similar degree in normal and COPD lung fibroblasts as well as in HFL-1 cells exposed or not exposed to cigarette smoke extract. Conclusion: These findings suggest that, in contrast to airway epithelial cells and monocytes/macrophages, HDAC2 is not required for budesonide to inhibit MMP and cytokine release by lung fibroblasts and this inhibitory pathway appears to be intact in cultured fibroblasts from COPD patients. These results also suggest that budesonide has the potential to modulate fibroblast-mediated tissue remodeling following airway inflammation in COPD, which is mediated via an HDAC2 independent pathway.

Original languageEnglish (US)
Pages (from-to)109-119
Number of pages11
JournalJournal of Inflammation Research
Volume6
Issue number1
DOIs
StatePublished - Aug 19 2013

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Histone Deacetylase 2
Budesonide
Anti-Inflammatory Agents
Fibroblasts
Lung
Matrix Metalloproteinase 1
Cytokines
Matrix Metalloproteinases
Chronic Obstructive Pulmonary Disease
Glucocorticoids
Matrix Metalloproteinase 3
Epithelial Cells
Interleukin-8
Interleukin-1
Monocytes
Interleukin-6
Tumor Necrosis Factor-alpha
RNA
Airway Remodeling
Alveolar Epithelial Cells

Keywords

  • Budesonide
  • Fibroblasts
  • HDAC2

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

Cite this

Anti-inflammatory effects of budesonide in human lung fibroblasts are independent of histone deacetylase 2. / Wang, Xingqi; Nelson, Amy; Weiler, Zachary M.; Patil, Amol N; Sato, Tadashi; Kanaji, Nobuhiro; Nakanishi, Masanori; Michalski, Joel; Farid, Maha; Basma, Hesham E; LeVan, Tricia D; Miller-Larsson, Anna; Wieslander, Elisabet; Muller, Kai Christian; Holz, Olaf; Magnussen, Helgo; Rabe, Klaus F.; Liu, Xiang-de; Rennard, Stephen I.

In: Journal of Inflammation Research, Vol. 6, No. 1, 19.08.2013, p. 109-119.

Research output: Contribution to journalArticle

Wang, X, Nelson, A, Weiler, ZM, Patil, AN, Sato, T, Kanaji, N, Nakanishi, M, Michalski, J, Farid, M, Basma, HE, LeVan, TD, Miller-Larsson, A, Wieslander, E, Muller, KC, Holz, O, Magnussen, H, Rabe, KF, Liu, X & Rennard, SI 2013, 'Anti-inflammatory effects of budesonide in human lung fibroblasts are independent of histone deacetylase 2', Journal of Inflammation Research, vol. 6, no. 1, pp. 109-119. https://doi.org/10.2147/JIR.S43736
Wang, Xingqi ; Nelson, Amy ; Weiler, Zachary M. ; Patil, Amol N ; Sato, Tadashi ; Kanaji, Nobuhiro ; Nakanishi, Masanori ; Michalski, Joel ; Farid, Maha ; Basma, Hesham E ; LeVan, Tricia D ; Miller-Larsson, Anna ; Wieslander, Elisabet ; Muller, Kai Christian ; Holz, Olaf ; Magnussen, Helgo ; Rabe, Klaus F. ; Liu, Xiang-de ; Rennard, Stephen I. / Anti-inflammatory effects of budesonide in human lung fibroblasts are independent of histone deacetylase 2. In: Journal of Inflammation Research. 2013 ; Vol. 6, No. 1. pp. 109-119.
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T1 - Anti-inflammatory effects of budesonide in human lung fibroblasts are independent of histone deacetylase 2

AU - Wang, Xingqi

AU - Nelson, Amy

AU - Weiler, Zachary M.

AU - Patil, Amol N

AU - Sato, Tadashi

AU - Kanaji, Nobuhiro

AU - Nakanishi, Masanori

AU - Michalski, Joel

AU - Farid, Maha

AU - Basma, Hesham E

AU - LeVan, Tricia D

AU - Miller-Larsson, Anna

AU - Wieslander, Elisabet

AU - Muller, Kai Christian

AU - Holz, Olaf

AU - Magnussen, Helgo

AU - Rabe, Klaus F.

AU - Liu, Xiang-de

AU - Rennard, Stephen I.

PY - 2013/8/19

Y1 - 2013/8/19

N2 - Objective and design: Reduced expression of histone deacetylase 2 (HDAC2) in alveolar macrophages and epithelial cells may account for reduced response of chronic obstructive pulmonary disease (COPD) patients to glucocorticoids. HDAC2 expression and its role in mediating glucocorticoid effects on fibroblast functions, however, has not been fully studied. This study was designed to investigate whether HDAC2 mediates glucocorticoid effects on release of inflammatory cytokines and matrix metalloproteinases (MMPs) from human lung fibroblasts. Methods: Human lung fibroblasts (HFL-1 cells) were stimulated with interleukin (IL)-1β plus tumor necrosis factor (TNF)-α in the presence or absence of the glucocorticoid budesonide. Cytokines (IL-6 and IL-8) were quantified by enzyme linked immunosorbent assay (ELISA) and MMPs (MMP-1 and MMP-3) by immunoblotting in culture medium. The role of HDAC2 was investigated using a pharmacologic inhibitor as well as a small interfering ribonucleic acid (siRNA) targeting HDAC2. Results: We have demonstrated that budesonide concentration-dependently (10-10-10-7 M) inhibited IL-6, IL-8, MMP-1, and MMP-3 release by HFL-1 cells in response to IL-1β plus TNF-a. While an HDAC inhibitor significantly blocked the inhibitory effect of budesonide on human bronchial epithelial cells (HBECs) and monocytes (THP-1 cells), it did not block the inhibitory effect of budesonide on release of cytokines and MMPs from HFL-1 cells. Similarly, an HDAC2-siRNA blocked budesonide inhibition of cytokine release in HBECs, but it did not block the inhibitory effect of budesonide on HFL-1 cytokine and MMP release. Furthermore, budesonide significantly blocked release of cytokines and MMPs to a similar degree in normal and COPD lung fibroblasts as well as in HFL-1 cells exposed or not exposed to cigarette smoke extract. Conclusion: These findings suggest that, in contrast to airway epithelial cells and monocytes/macrophages, HDAC2 is not required for budesonide to inhibit MMP and cytokine release by lung fibroblasts and this inhibitory pathway appears to be intact in cultured fibroblasts from COPD patients. These results also suggest that budesonide has the potential to modulate fibroblast-mediated tissue remodeling following airway inflammation in COPD, which is mediated via an HDAC2 independent pathway.

AB - Objective and design: Reduced expression of histone deacetylase 2 (HDAC2) in alveolar macrophages and epithelial cells may account for reduced response of chronic obstructive pulmonary disease (COPD) patients to glucocorticoids. HDAC2 expression and its role in mediating glucocorticoid effects on fibroblast functions, however, has not been fully studied. This study was designed to investigate whether HDAC2 mediates glucocorticoid effects on release of inflammatory cytokines and matrix metalloproteinases (MMPs) from human lung fibroblasts. Methods: Human lung fibroblasts (HFL-1 cells) were stimulated with interleukin (IL)-1β plus tumor necrosis factor (TNF)-α in the presence or absence of the glucocorticoid budesonide. Cytokines (IL-6 and IL-8) were quantified by enzyme linked immunosorbent assay (ELISA) and MMPs (MMP-1 and MMP-3) by immunoblotting in culture medium. The role of HDAC2 was investigated using a pharmacologic inhibitor as well as a small interfering ribonucleic acid (siRNA) targeting HDAC2. Results: We have demonstrated that budesonide concentration-dependently (10-10-10-7 M) inhibited IL-6, IL-8, MMP-1, and MMP-3 release by HFL-1 cells in response to IL-1β plus TNF-a. While an HDAC inhibitor significantly blocked the inhibitory effect of budesonide on human bronchial epithelial cells (HBECs) and monocytes (THP-1 cells), it did not block the inhibitory effect of budesonide on release of cytokines and MMPs from HFL-1 cells. Similarly, an HDAC2-siRNA blocked budesonide inhibition of cytokine release in HBECs, but it did not block the inhibitory effect of budesonide on HFL-1 cytokine and MMP release. Furthermore, budesonide significantly blocked release of cytokines and MMPs to a similar degree in normal and COPD lung fibroblasts as well as in HFL-1 cells exposed or not exposed to cigarette smoke extract. Conclusion: These findings suggest that, in contrast to airway epithelial cells and monocytes/macrophages, HDAC2 is not required for budesonide to inhibit MMP and cytokine release by lung fibroblasts and this inhibitory pathway appears to be intact in cultured fibroblasts from COPD patients. These results also suggest that budesonide has the potential to modulate fibroblast-mediated tissue remodeling following airway inflammation in COPD, which is mediated via an HDAC2 independent pathway.

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KW - Fibroblasts

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