| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
|
|
|
|||||||
|
|||||||||
* Department of Microbiology and Immunology, University of Louisville School of Medicine, Louisville, KY 40292; and
Cellular Stress Group, Medical Research Council Clinical Sciences Centre, Imperial College, Hammersmith Hospital, London, United Kingdom
Herein, we demonstrate a role of AMP-activated protein kinase (AMPK) as a potent counterregulator of inflammatory signaling pathways in macrophages. Stimulation of macrophages with anti-inflammatory cytokines (i.e., IL-10 and TGFβ) resulted in the rapid phosphorylation/activation of AMPK, whereas stimulation of macrophages with a proinflammatory stimulus (LPS) resulted in AMPK dephosphorylation/inactivation. Inhibition of AMPK
expression by RNA interference dramatically increased the mRNA levels of LPS-induced TNF-, IL-6, and cyclooxygenase-2. Likewise, expression of a dominant negative AMPK1 in macrophages enhanced TNF- and IL-6 protein synthesis in response to LPS stimulation, while diminishing the production of IL-10. In contrast, transfection of macrophages with a constitutively active form of AMPK1 resulted in decreased LPS-induced TNF- and IL-6 production, and heightened production of IL-10. In addition, we found that AMPK negatively regulated LPS-induced I
B- degradation and positively regulated Akt activation, accompanied by inhibition of glycogen synthase kinase β and activation of CREB. Thus, AMPK directs signaling pathways in macrophages in a manner that suppresses proinflammatory responses and promotes macrophage polarization to an anti-inflammatory functional phenotype.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 This work was supported by National Institutes of Health Grant AI048850 (to J.S.), by an American Heart Association Predoctoral Fellowship (to D.S.), and in part, by the Commonwealth of Kentucky Research Challenge Trust Fund (to J.S. and R.D.S.).
2 Address correspondence and reprint requests to Dr. Jill Suttles, University of Louisville School of Medicine, Louisville, KY 40292. E-mail address: jill.suttles{at}louisville.edu
3 Abbreviations used in this paper: AMPK, AMP-activated protein kinase; ACC, acetyl-CoA carboxylase; COX-2, cyclooxygenase-2; GSK3-β, glycogen synthase kinase β; IKK, inhibitory B kinase; AICAR, 5-aminoimidazole-4-carboxamide ribose; siRNA, small interfering RNA; DN-AMPK1, dominant negative AMPK1; CA-AMPK1, constitutively active AMPK1; CAMKKβ, calmodulin-dependent protein kinase kinase β; mTOR, mammalian target of rapamycin; mTORC, mTOR complex; TSC2, tuberous sclerosis complex-2.
Related articles in The JI:
This article has been cited by other articles:
|
|
 |
|
  Y. Alvarez, C. Municio, S. Alonso, M. Sanchez Crespo, and N. Fernandez The Induction of IL-10 by Zymosan in Dendritic Cells Depends on CREB Activation by the Coactivators CREB-Binding Protein and TORC2 and Autocrine PGE2 J. Immunol., July 15, 2009; 183(2): 1471 - 1479. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
N. Nath, M. Khan, M. K. Paintlia, M. N. Hoda, and S. Giri Metformin Attenuated the Autoimmune Disease of the Central Nervous System in Animal Models of Multiple Sclerosis J. Immunol., June 15, 2009; 182(12): 8005 - 8014. [Abstract] [Full Text] [PDF]
|
|
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
