title: Dihydroartemisinin ameliorates inflammatory disease by its reciprocal effects on Th and regulatory T cell function via modulating the mammalian target of rapamycin pathway.
abstract: Dihydroartemisinin (DHA) is an important derivative of the herb medicine Artemisia annua L., used in ancient China. DHA is currently used worldwide to treat malaria by killing malaria-causing parasites. In addition to this prominent effect, DHA is thought to regulate cellular functions, such as angiogenesis, tumor cell growth, and immunity. Nonetheless, how DHA affects T cell function remains poorly understood. We found that DHA potently suppressed Th cell differentiation in vitro. Unexpectedly, however, DHA greatly promoted regulatory T cell (Treg) generation in a manner dependent on the TGF-βR:Smad signal. In addition, DHA treatment effectively reduced onset of experimental autoimmune encephalomyelitis (EAE) and ameliorated ongoing EAE in mice. Administration of DHA significantly decreased Th but increased Tregs in EAE-inflicted mice, without apparent global immune suppression. Moreover, DHA modulated the mammalian target of rapamycin (mTOR) pathway, because mTOR signal was attenuated in T cells upon DHA treatment. Importantly, enhanced Akt activity neutralized DHA-mediated effects on T cells in an mTOR-dependent fashion. This study therefore reveals a novel immune regulatory function of DHA in reciprocally regulating Th and Treg cell generation through the modulating mTOR pathway. It addresses how DHA regulates immune function and suggests a new type of drug for treating diseases in which mTOR activity is to be tempered.
authors.affiliation: Lineberger Comprehensive Cancer Center and Department of Microbiology and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
authors.forename: Yan G
authors.initials: YG
authors.lastname: Zhao
authors.forename: Yunqi
authors.initials: Y
authors.lastname: Wang
authors.forename: Zengli
authors.initials: Z
authors.lastname: Guo
authors.forename: Ai-di
authors.initials: AD
authors.lastname: Gu
authors.forename: Han C
authors.initials: HC
authors.lastname: Dan
authors.forename: Albert S
authors.initials: AS
authors.lastname: Baldwin
authors.forename: Weidong
authors.initials: W
authors.lastname: Hao
authors.forename: Yisong Y
authors.initials: YY
authors.lastname: Wan
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D037621:Artemisinins / Q000494:pharmacology*; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000276:immunology / Q000473:pathology / Q000517:prevention & control; D007249:Inflammation / Q000276:immunology / Q000473:pathology / Q000517:prevention & control*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008969:Molecular Sequence Data; D015398:Signal Transduction / Q000187:drug effects / Q000276:immunology*; D006377:T-Lymphocytes, Helper-Inducer / Q000187:drug effects* / Q000276:immunology*; D050378:T-Lymphocytes, Regulatory / Q000187:drug effects* / Q000276:immunology* / Q000473:pathology; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism* / Q000502:physiology
chemical_list: D037621:Artemisinins; C039060:artenimol; C031327:artemisinin; C546843:mTOR protein, mouse; D058570:TOR Serine-Threonine Kinases