NDLI: Regulation of inflammatory response by 3-methyladenine involves the coordinative actions on Akt and glycogen synthase kinase 3ß rather than autophagy.

Content Provider	World Health Organization (WHO)-Global Index Medicus
Author	Lin, Yi-Chieh Kuo, Hsuan-Cheng Wang, Jang-Shiun Lin, Wan-Wan
Description	Country affiliation: Taiwan Author Affiliation: Lin YC ( Department of Pharmacology, College of Medicine, National Taiwan University, Taipei 10051, Taiwan.)
Abstract	3-Methyladenine (3-MA) is one of the most commonly used inhibitors in autophagy research today. However, rather than inhibiting class III PI3K that is involved in autophagy suppression, 3-MA might also interfere with class I PI3K and consequently augment autophagy flux. In this study, we aim to get a thorough understanding on the action mechanisms of 3-MA in TLR4-mediated inflammatory responses in RAW264.7 macrophages and, moreover, to decipher the action of 3-MA in modulation of autophagy. We found that 3-MA could enhance LPS-induced NF-κB activation and production of TNF- , inducible NO synthase (iNOS), cyclooxygenase-2, IL-1ß, and IL-12. In contrast, 3-MA suppressed LPS-induced IFN-ß production and STAT signaling. Studies revealed that 3-MA can, through inhibition of Akt as a result of class I PI3K interference, positively regulate p38, JNK, and p65, but negatively regulate TANK-binding kinase 1 and IFN regulatory factor 3 mediated by TLR4. As glycogen synthase kinase 3ß (GSK3ß) is an important Akt substrate, we further explored its involvement in the actions of 3-MA. 3-MA was found to enhance LPS-induced NF-κB activation, iNOS, and pro-IL-1ß expression, and these actions were reversed by either GSK3ß inhibitors or small interfering GSK3ß. Lastly, we demonstrated that 3-MA acts as an autophagy inducer in RAW264.7 macrophages, but the stimulating effects on NF-κB activation and iNOS and cyclooxygenase-2 expression were not affected in LPS-stimulated macrophages with small interfering autophagy protein-5 treatment. These results not only shed new light on the action mechanisms of 3-MA to differentially regulate inflammatory outcomes derived from TLR4-mediated MyD88 and Toll/IL-1R domain-containing adapter inducing IFN-ß pathways, but also highlight the necessity to check autophagy status upon taking 3-MA as a general autophagy inhibitor.
ISSN	00221767
e-ISSN	15506606
Journal	The Journal of Immunology
Issue Number	8
Volume Number	189
Language	English
Publisher	The American Association of Immunologists
Publisher Date	2012-10-15
Publisher Place	United States
Access Restriction	Open
Subject Keyword	Adenine Analogs & Derivatives Autophagy Immunology Glycogen Synthase Kinase 3 Metabolism Inflammation Mediators Physiology Proto-oncogene Proteins C-akt Pharmacology Animals Drug Effects Cell Line Lipopolysaccharides Macrophages Enzymology Mice Primary Cell Culture Signal Transduction Up-regulation Research Support, Non-u.s. Gov't Discipline Immunology
Content Type	Text
Resource Type	Article
Subject	Immunology and Allergy Immunology

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