Deregulation of Tpl2 and NF-kappaB signaling and induction of macrophage apoptosis by the anti-depressant drug lithium.
Lithium is an anti-depressant drug that also possesses immunomodulatory functions. The anti-inflammatory effect of lithium is thought to involve activation of the transcription factor CREB, although the underlying mechanism is incompletely understood. We show here that in macrophages lithium stimulates Tpl2, a MAP kinase kinase kinase (MAP3K) known to mediate activation of extracellular signal regulated kinase (ERK) and the downstream target CREB. Lithium activates Tpl2 by inducing degradation of p105, an NF-kappaB precursor protein that functions as a physiological inhibitor of Tpl2. This novel function of lithium does not involve inhibition of a well-characterized lithium target, GSK3beta, since other known GSK3beta inhibitors do not induce p105 degradation or Tpl2 activation. Lithium also promotes the activation of Tpl2 and ERK by the TLR4 ligand LPS. On the other hand, prolonged incubation of macrophages with lithium results in dramatic loss of p105 and inhibition of LPS-stimulated NF-kappaB activation. Consequently, lithium both attenuates LPS-mediated pro-inflammatory gene induction and induces apoptosis in macrophages. These results provide novel insight into the anti-inflammatory function of lithium.
Zhang
Minying
M
Department of Immunology, The University of Texas MD Anderson Cancer Center, 7455 Fannin Street, Box 902, Houston TX 77030, United States.
Jin
Wei
W
Zhou
Xiaofei
X
Yu
Jiayi
J
Lee
Andrew J
AJ
Sun
Shao-Cong
SC
D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D000928:Antidepressive Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D016207:Cytokines / Q000096:biosynthesis / Q000235:genetics; D004789:Enzyme Activation / Q000187:drug effects; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D008070:Lipopolysaccharides / Q000633:toxicity; D018021:Lithium Chloride / Q000494:pharmacology*; D020930:MAP Kinase Kinase Kinases / Q000502:physiology*; D020935:MAP Kinase Signaling System / Q000187:drug effects*; D008264:Macrophages / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D016328:NF-kappa B / Q000502:physiology*; D052002:NF-kappa B p50 Subunit / Q000037:antagonists & inhibitors / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D011499:Protein Processing, Post-Translational / Q000187:drug effects; D011518:Proto-Oncogene Proteins / Q000502:physiology*; D013047:Specific Pathogen-Free Organisms; D051197:Toll-Like Receptor 4 / Q000502:physiology
D000894:Anti-Inflammatory Agents, Non-Steroidal; D000928:Antidepressive Agents; D016207:Cytokines; D008070:Lipopolysaccharides; D016328:NF-kappa B; D052002:NF-kappa B p50 Subunit; D011518:Proto-Oncogene Proteins; C493487:Tlr4 protein, mouse; D051197:Toll-Like Receptor 4; D000071679:Glycogen Synthase Kinase 3 beta; C000605507:Gsk3b protein, mouse; D048049:Extracellular Signal-Regulated MAP Kinases; D020930:MAP Kinase Kinase Kinases; C489843:Map3k8 protein, mouse; D038362:Glycogen Synthase Kinase 3; D018021:Lithium Chloride