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Sci. Signal., 5 July 2011
Vol. 4, Issue 180, p. ra44
[DOI: 10.1126/scisignal.2001450]

RESEARCH ARTICLES

Identification of a Lysosomal Pathway That Modulates Glucocorticoid Signaling and the Inflammatory Response

Yuanzheng He1*{dagger}, Yong Xu1*, Chenghai Zhang1, Xiang Gao1, Karl J. Dykema2, Katie R. Martin3, Jiyuan Ke1, Eric A. Hudson4, Sok Kean Khoo4,5, James H. Resau4, Arthur S. Alberts6, Jeffrey P. MacKeigan3, Kyle A. Furge2, and H. Eric Xu1,7{dagger}

1 Laboratory of Structural Sciences, Van Andel Research Institute, 333 Bostwick Avenue Northeast, Grand Rapids, MI 49503, USA.
2 Laboratory of Computational Biology, Van Andel Research Institute, Grand Rapids, MI 49503, USA.
3 Laboratory of Systems Biology, Van Andel Research Institute, Grand Rapids, MI 49503, USA.
4 Laboratory of Analytical, Cellular, and Molecular Microscopy, Van Andel Research Institute, Grand Rapids, MI 49503, USA.
5 Laboratory of Microarray Technology, Van Andel Research Institute, Grand Rapids, MI 49503, USA.
6 Laboratory of Cell Structure and Signal Integration, Van Andel Research Institute, Grand Rapids, MI 49503, USA.
7 VARI/SIMM Center, Center for Structure and Function of Drug Targets, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, P. R. China.

* These authors contributed equally to this work.

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.

{dagger} To whom correspondence should be addressed. E-mail: eric.xu{at}vai.org (H.E.X.); ajian.he{at}vai.org (Y.H.)

Citation: Y. He, Y. Xu, C. Zhang, X. Gao, K. J. Dykema, K. R. Martin, J. Ke, E. A. Hudson, S. K. Khoo, J. H. Resau, A. S. Alberts, J. P. MacKeigan, K. A. Furge, H. E. Xu, Identification of a Lysosomal Pathway That Modulates Glucocorticoid Signaling and the Inflammatory Response. Sci. Signal. 4, ra44 (2011).

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