Clozapine increases macrophage migration inhibitory factor (MIF) expression via increasing histone acetylation of MIF promoter in astrocytes

Okazaki, Satoshi; Boku, Shuken; Otsuka, Ikuo; Horai, Tadasu; Kimura, Atsushi; Shimmyo, Naofumi; Yamaki, Naruhisa; Hishimoto, Akitoyo

doi:10.1016/j.jpsychires.2021.01.033

Cited by 7 publications

(11 citation statements)

References 38 publications

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“…These findings suggest that MIF may function as a physiological protective factor against SCZ risk [35]. The present study showed that SNP rs17004038 in the HRE of the MIF gene is significantly more common in patients with SCZ, and that this SNP inhibits hypoxia-induced MIF expression in PCAs from mice.…”

Section: Plos Onesupporting

confidence: 58%

“…Previous studies have shown that blood MIF is increased in patients with SCZ, including initial-onset, drug-naive patients [32,33]. Our previous studies showed that antipsychotic dosage positively correlated with MIF blood levels, that a higher-expression polymorphism of the MIF promoter is significantly lower frequent in female patients with adolescent-onset SCZ [34], and that clozapine and other antipsychotics increased MIF expression in PCAs [35].…”

Section: Discussionmentioning

confidence: 79%

“…We also reported that the serum MIF level is higher in patients with SCZ and positively correlated with antipsychotic doses, and that a higherexpression allele of the MIF−794CATT 5−8 microsatellite (rs5844572) in the MIF promoter is significantly lower frequent in female patients with adolescent-onset SCZ [34]. Furthermore, we have shown that clozapine, an atypical antipsychotic, increased MIF expression via histone acetylation in neonatal mice-derived primary cultured astrocytes (PCAs) [35]. Taken together, these findings suggest that MIF may have an important role in the pathophysiology of SCZ and the functional mechanisms of antipsychotics.…”

Section: Introductionmentioning

confidence: 94%

“…PCAs were prepared from neonatal C57BL/6J mice as described elsewhere [35,41]. Briefly, the isolated forebrain was minced and incubated with DNase I (FUJIFILM Wako Pure Chemical) and trypsin (Thermo Fisher Scientific) for dissociation.…”

Section: Cell Culturementioning

confidence: 99%

“…The ChIP assay was performed as described elsewhere [35]. Briefly, PCAs were seeded onto a non-coated 90-mm dish (2 × 10 6 cells/dish) in DMEM/F12 supplemented with 10% FBS and PS.…”

Section: Chromatin Immunoprecipitation (Chip) Assaymentioning

confidence: 99%

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Polymorphisms in the hypoxia inducible factor binding site of the macrophage migration inhibitory factor gene promoter in schizophrenia

et al. 2022

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Background Macrophage migration inhibitory factor (MIF) is a multifunctional cytokine that promotes neurogenesis and neuroprotection. MIF is predominantly expressed in astrocytes in the brain. The serum MIF level and microsatellites/single nucleotide polymorphisms (SNPs) in the MIF gene promoter region are known to be associated with schizophrenia (SCZ). Interestingly, previous studies reported that hypoxia, an environmental risk factor for SCZ, induced MIF expression through binding of the hypoxia inducible factor (HIF)-1 to the hypoxia response element (HRE) in the MIF promoter. Methods We investigated the involvement of MIF in SCZ while focusing on the HIF pathway. First, we conducted an association study of the SNP rs17004038 (C>A) in the HRE of the MIF promoter between 1758 patients with SCZ and 1507 controls. Next, we investigated the effect of hypoxia on MIF expression in primary cultured astrocytes derived from neonatal mice forebrain. Results SNP rs17004038 was significantly associated with SCZ (p = 0.0424, odds ratio = 1.445), indicating that this SNP in the HRE of the MIF promoter was a genetic risk factor for SCZ. Hypoxia induced MIF mRNA expression and MIF protein production and increased HIF-1 binding to the MIF promoter, while the activity of the MIF promoter was suppressed by mutations in the HRE and by deletion of the HRE in astrocytes. Conclusion These results suggest that SNP rs17004038 in the HRE of the MIF promoter was significantly associated with SCZ and may be involved in the pathophysiology of SCZ via suppression of hypoxia and HIF pathway-induced MIF expression.

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Section: Plos Onesupporting

confidence: 58%

Section: Discussionmentioning

confidence: 79%

Section: Introductionmentioning

confidence: 94%

Section: Cell Culturementioning

confidence: 99%

“…The ChIP assay was performed as described elsewhere [35]. Briefly, PCAs were seeded onto a non-coated 90-mm dish (2 × 10 6 cells/dish) in DMEM/F12 supplemented with 10% FBS and PS.…”

Section: Chromatin Immunoprecipitation (Chip) Assaymentioning

confidence: 99%

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