PMID- 22826223 OWN - NLM STAT- MEDLINE DCOM- 20121015 LR - 20211021 IS - 1091-6490 (Electronic) IS - 0027-8424 (Print) IS - 0027-8424 (Linking) VI - 109 IP - 32 DP - 2012 Aug 7 TI - Macrophage migration inhibitory factor mediates the antidepressant actions of voluntary exercise. PG - 13094-9 LID - 10.1073/pnas.1205535109 [doi] AB - Voluntary exercise is known to have an antidepressant effect. However, the underlying mechanism for this antidepressant action of exercise remains unclear, and little progress has been made in identifying genes that are directly involved. We have identified macrophage migration inhibitory factor (MIF) by analyzing existing mRNA microarray data and confirmed the augmented expression of selected genes under two experimental conditions: voluntary exercise and electroconvulsive seizure. A proinflammatory cytokine, MIF is expressed in the central nervous system and involved in innate and adaptive immune responses. A recent study reported that MIF is involved in antidepressant-induced hippocampal neurogenesis, but the mechanism remains elusive. In our data, tryptophan hydroxylase 2 (Tph2) and brain-derived neurotrophic factor (Bdnf) expression were induced after MIF treatment in vitro, as well as during both exercise and electroconvulsive seizure in vivo. This increment of Tph2 was accompanied by increases in the levels of total serotonin in vitro. Moreover, the MIF receptor CD74 and the ERK1/2 pathway mediate the MIF-induced Tph2 and Bdnf gene expression as well as serotonin content. Experiments in Mif(-/-) mice revealed depression-like behaviors and a blunted antidepressant effect of exercise, as reflected by changes in Tph2 and Bdnf expression in the forced swim test. In addition, administration of recombinant MIF protein produced antidepressant-like behavior in rats in the forced swim test. Taken together, these results suggest a role of MIF in mediating the antidepressant action of exercise, probably by enhancing serotonin neurotransmission and neurotrophic factor-induced neurogenesis in the brain. FAU - Moon, Hyo Youl AU - Moon HY AD - School of Interdisciplinary Bioscience and Bioengineering, Pohang University of Science and Technology, Pohang 790-784, Korea. FAU - Kim, Se Hyun AU - Kim SH FAU - Yang, Yong Ryoul AU - Yang YR FAU - Song, Parkyong AU - Song P FAU - Yu, Hyun Sook AU - Yu HS FAU - Park, Hong Geun AU - Park HG FAU - Hwang, Onyou AU - Hwang O FAU - Lee-Kwon, Whaseon AU - Lee-Kwon W FAU - Seo, Jeong Kon AU - Seo JK FAU - Hwang, Daehee AU - Hwang D FAU - Choi, Jang Hyun AU - Choi JH FAU - Bucala, Richard AU - Bucala R FAU - Ryu, Sung Ho AU - Ryu SH FAU - Kim, Yong Sik AU - Kim YS FAU - Suh, Pann-Ghill AU - Suh PG LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20120723 PL - United States TA - Proc Natl Acad Sci U S A JT - Proceedings of the National Academy of Sciences of the United States of America JID - 7505876 RN - 0 (Brain-Derived Neurotrophic Factor) RN - 0 (DNA Primers) RN - 0 (Macrophage Migration-Inhibitory Factors) RN - 0 (Recombinant Proteins) RN - 333DO1RDJY (Serotonin) RN - EC 1.14.16.4 (Tryptophan Hydroxylase) RN - EC 1.14.16.4 (tph2 protein, rat) RN - EC 5.3.- (Intramolecular Oxidoreductases) RN - EC 5.3.2.1 (Mif protein, mouse) SB - IM CIN - Nat Rev Neurosci. 2012 Sep;13(9):602. PMID: 22895476 MH - Analysis of Variance MH - Animals MH - Blotting, Western MH - Brain-Derived Neurotrophic Factor/metabolism MH - Cells, Cultured MH - DNA Primers/genetics MH - Depression/*therapy MH - Electroshock/*methods MH - Immunohistochemistry MH - Infusions, Intraventricular MH - Intramolecular Oxidoreductases/administration & dosage/genetics/*pharmacology MH - Macrophage Migration-Inhibitory Factors/administration & dosage/genetics/*pharmacology MH - Male MH - Mice MH - Mice, Inbred C57BL MH - Mice, Knockout MH - Motor Activity/drug effects/*physiology MH - Rats MH - Rats, Sprague-Dawley MH - Real-Time Polymerase Chain Reaction MH - Recombinant Proteins/pharmacology MH - Reverse Transcriptase Polymerase Chain Reaction MH - Serotonin/metabolism MH - Tryptophan Hydroxylase/metabolism PMC - PMC3420190 COIS- The authors declare no conflict of interest. EDAT- 2012/07/25 06:00 MHDA- 2012/10/16 06:00 PMCR- 2012/07/23 CRDT- 2012/07/25 06:00 PHST- 2012/07/25 06:00 [entrez] PHST- 2012/07/25 06:00 [pubmed] PHST- 2012/10/16 06:00 [medline] PHST- 2012/07/23 00:00 [pmc-release] AID - 1205535109 [pii] AID - 201205535 [pii] AID - 10.1073/pnas.1205535109 [doi] PST - ppublish SO - Proc Natl Acad Sci U S A. 2012 Aug 7;109(32):13094-9. doi: 10.1073/pnas.1205535109. Epub 2012 Jul 23.