Transcriptomics

Dataset Information

35

Potentiation of glucocorticoid signaling by chloroquine via inhibition of lysosomes


ABSTRACT: Anti-malaria drug chloroquine has been used as an anti-inflammatory agent for treating systemic lupus erythematosus and rheumatoid arthritis, without clear mechanism of action. Here we report that chloroquine potently inhibits the expression of proinflammatory cytokines through transrepression of glucocorticoid receptor (GR). Instead of direct binding to GR, chloroquine synergistically activates glucocorticoid signaling via inhibition of lysosomal functions. In mouse collagen induced arthritis model, chloroquine synergizes the therapeutic effects of glucocorticoid. Lysosomal inhibition by bafilomycin A1, an inhibitor of V-type ATPase, or by knockdown of transcription factor EB (TFEB), a master activator of lysosomal biogenesis, mimics the effects of chloroquine. These results reveal an unexpected regulation of glucocorticoid signaling by lysosomes and provide a mechanistic basis for treating inflammation and autoimmune diseases by combination of glucocorticoids and lysosomal inhibitors. Macrophage THP-1 cells treated with LPS, chloroquine and dexamethasone.

ORGANISM(S): Homo sapiens  

SUBMITTER: Karl Dykema   

PROVIDER: E-GEOD-24579 | ArrayExpress| 2012-06-26

SECONDARY ACCESSION(S): GSE24579PRJNA132479

REPOSITORIES: GEO, ArrayExpress

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Publications

Identification of a lysosomal pathway that modulates glucocorticoid signaling and the inflammatory response.

He Yuanzheng Y   Xu Yong Y   Zhang Chenghai C   Gao Xiang X   Dykema Karl J KJ   Martin Katie R KR   Ke Jiyuan J   Hudson Eric A EA   Khoo Sok Kean SK   Resau James H JH   Alberts Arthur S AS   MacKeigan Jeffrey P JP   Furge Kyle A KA   Xu H Eric HE  

Science signaling 20110705 180


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 inhibit  ...[more]

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