• ホーム
  • 検索結果
  • Lysosomotropic beta blockers induce oxidative stress and IL23A production in Langerhans cells.

Lysosomotropic beta blockers induce oxidative stress and IL23A production in Langerhans cells.

Autophagy (2019-11-02)
Gerrit Müller, Charlotte Lübow, Günther Weindl
要旨

Oxidative stress and Th17 cytokines are important mediators of inflammation. Treatment with beta-adrenoceptor (ADRB) antagonists (beta-blockers) is associated with induction or aggravation of psoriasis-like skin inflammation, yet the underlying mechanisms are poorly understood. Herein, we identify lysosomotropic beta-blockers as critical inducers of IL23A in human monocyte-derived Langerhans-like cells under sterile-inflammatory conditions. Cytokine release was not mediated by cAMP, suggesting the involvement of ADRB-independent pathways. NFKB/NF-κB and MAPK14/p38 activation was required for propranolol-induced IL23A secretion whereas the NLRP3 inflammasome was dispensable. MAPK14 regulated recruitment of RELB to IL23A promoter regions. Without affecting the ubiquitin-proteasome pathway, propranolol increased lysosomal pH and induced a late-stage block in macroautophagy/autophagy. Propranolol specifically induced reactive oxygen species production, which was critical for IL23A secretion, in Langerhans-like cells. Our findings provide insight into a potentially crucial immunoregulatory mechanism in cutaneous dendritic cells that may explain how lysosomotropic drugs regulate inflammatory responses. ATF: activating transcription factor; DC: dendritic cell; ChIP: chromatin immunoprecipitation; gDNA: genomic DNA; IL: interleukin; LAMP1: lysosomal associated membrane protein 1; LC: Langerhans cell; LPS: lipopolysaccharide; MAP1LC3/LC3: microtubule associated protein 1 light chain 3; MAPK: mitogen-activated protein kinase; MoDC: monocyte-derived DC; MoLC: monocyte-derived Langerhans-like cell; mtDNA: mitochondrial DNA; NAC: N-acetyl-L-cysteine; NLRP3: NLR family pyrin domain containing 3; PBMC: peripheral blood mononuclear cell; PI: propidium iodide; PYCARD/ASC: PYD and CARD domain containing; qRT-PCR: quantitative real-time PCR; ROS: reactive oxygen species; SQSTM1/p62: sequestosome 1; TLR: Toll-like receptor; TRAF6: TNF receptor associated factor 6; TNF: tumor necrosis factor; Ub: ubiquitin.

材料
製品番号
ブランド
製品内容

Sigma-Aldrich
ダルベッコリン酸緩衝生理食塩水, Modified, without calcium chloride and magnesium chloride, liquid, sterile-filtered, suitable for cell culture
Sigma-Aldrich
ペニシリン-ストレプトマイシン, Solution stabilized, with 10,000 units penicillin and 10 mg streptomycin/mL, 0.1 μm filtered, BioReagent, suitable for cell culture
Sigma-Aldrich
L-グルタミン 溶液, 200 mM, solution, sterile-filtered, BioXtra, suitable for cell culture
Sigma-Aldrich
RPMI-1640培地, With sodium bicarbonate, without L-glutamine, liquid, sterile-filtered, suitable for cell culture
Sigma-Aldrich
過硫酸アンモニウム, for molecular biology, suitable for electrophoresis, ≥98%
Sigma-Aldrich
ホルムアルデヒド 溶液, for molecular biology, 36.5-38% in H2O
Sigma-Aldrich
クロロキン 二リン酸塩, powder or crystals, 98.5-101.0% (EP)
Sigma-Aldrich
FBS Superior, Supplemented FBS, EU approved
Sigma-Aldrich
MG-132、既製の溶液, ≥90% (HPLC)
SAFC
L-Glutamine Solution 200 mM, 29.23 mg/mL in saline, solution, suitable for cell culture
Sigma-Aldrich
SB 202190, ≥98% (HPLC)
Sigma-Aldrich
MitoTEMPO, ≥98% (HPLC)
Sigma-Aldrich
トリパンブルー, powder, BioReagent, suitable for cell culture
Sigma-Aldrich
Z-Leu-Leu-Leu-al, ≥90% (HPLC)
Sigma-Aldrich
SP600125, ≥98% (HPLC)
Sigma-Aldrich
Bay 11-7082, ≥98% (HPLC), powder
Sigma-Aldrich
Practolol, ≥95% (HPLC)
Sigma-Aldrich
アミロイドタンパク質非Aβ成分, ≥80% (HPLC)