title: Identification of a lysosomal pathway that modulates glucocorticoid signaling and the inflammatory response.
abstract: The antimalaria drug chloroquine has been used as an anti-inflammatory agent for treating systemic lupus erythematosus and rheumatoid arthritis. We report that chloroquine promoted the transrepression of proinflammatory cytokines by the glucocorticoid receptor (GR). In a mouse collagen-induced arthritis model, chloroquine enhanced the therapeutic effects of glucocorticoid treatment. By inhibiting lysosome function, chloroquine synergistically activated glucocorticoid signaling. Lysosomal inhibition by either bafilomycin A1 (an inhibitor of the vacuolar adenosine triphosphatase) or knockdown of transcription factor EB (TFEB, a master activator of lysosomal biogenesis) mimicked the effects of chloroquine. The abundance of the GR, as well as that of the androgen receptor and estrogen receptor, correlated with changes in lysosomal biogenesis. Thus, we showed that glucocorticoid signaling is regulated by lysosomes, which provides a mechanistic basis for treating inflammation and autoimmune diseases with a combination of glucocorticoids and lysosomal inhibitors.
authors: Laboratory of Structural Sciences, Van Andel Research Institute, 333 Bostwick Avenue Northeast, Grand Rapids, MI 49503, USA.
authors: Yuanzheng
authors: Y
authors: He
authors: Yong
authors: Y
authors: Xu
authors: Chenghai
authors: C
authors: Zhang
authors: Xiang
authors: X
authors: Gao
authors: Karl J
authors: KJ
authors: Dykema
authors: Katie R
authors: KR
authors: Martin
authors: Jiyuan
authors: J
authors: Ke
authors: Eric A
authors: EA
authors: Hudson
authors: Sok Kean
authors: SK
authors: Khoo
authors: James H
authors: JH
authors: Resau
authors: Arthur S
authors: AS
authors: Alberts
authors: Jeffrey P
authors: JP
authors: MacKeigan
authors: Kyle A
authors: KA
authors: Furge
authors: H Eric
authors: HE
authors: Xu
mesh_terms: D000818:Animals; D018501:Antirheumatic Agents; D001169:Arthritis, Experimental / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D002738:Chloroquine / Q000494:pharmacology / Q000627:therapeutic use*; D016207:Cytokines; D005938:Glucocorticoids / Q000378:metabolism* / Q000627:therapeutic use; D007249:Inflammation; D008247:Lysosomes / Q000187:drug effects* / Q000378:metabolism / Q000502:physiology; D051379:Mice; D011965:Receptors, Glucocorticoid; D015398:Signal Transduction
chemical_list: D018501:Antirheumatic Agents; D016207:Cytokines; D005938:Glucocorticoids; D011965:Receptors, Glucocorticoid; D002738:Chloroquine