Regulation of Human Formyl Peptide Receptor 1 Synthesis: Role of Single Nucleotide Polymorphisms, Transcription Factors, and Inflammatory Mediators

The gene encoding the human formyl peptide receptor 1 (FPR1) is heterogeneous, containing numerous single nucleotide polymorphisms (SNPs). Here, we examine the effect of these SNPs on gene transcription and protein translation. We also identify gene promoter sequences and putative FPR1 transcription factors. To test the effect of codon bias and codon pair bias on FPR1 expression, four FPR1 genetic variants were expressed in human myeloid U937 cells fused to a reporter gene encoding firefly luciferase. No significant differences in luciferase activity were detected, suggesting that the translational regulation and protein stability of FPR1 are modulated by factors other than the SNP codon bias and the variant amino acid properties. Deletion and mutagenesis analysis of the FPR1 promoter showed that a CCAAT box is not required for gene transcription. A −88/41 promoter construct resulted in the strongest transcriptional activity, whereas a −72/41 construct showed large reduction in activity. The region between −88 and −72 contains a consensus binding site for the transcription factor PU.1. Mutagenesis of this site caused significant reduction in reporter gene expression. The PU.1 binding was confirmed in vivo by chromatin immunoprecipitation, and the binding to nucleotides −84 to −76 (TTCCTATTT) was confirmed in vitro by an electrophoretic mobility shift assay. Thus, similar to many other myeloid genes, FPR1 promoter activity requires PU.1. Two single nucleotide polymorphisms at −56 and −54 did not significantly affect FPR1 gene expression, despite differences in binding of transcription factor IRF1 in vitro. Inflammatory mediators such as interferon-γ, tumor necrosis factor-α, and lipopolysaccharide did not increase FPR1 promoter activity in myeloid cells, whereas differentiation induced by DMSO and retinoic acid enhanced the activity. This implies that the expression of FPR1 in myeloid cells is developmentally regulated, and that the differentiated cells are equipped for immediate response to microbial infections

Functioning in patients with major depression treated with duloxetine or a selective serotonin reuptake inhibitor in East Asia

Diego Novick,1 William Montgomery,2 Josep Maria Haro,3 Maria Victoria Moneta,3 Gang Zhu,4 Li Yue,5 Jihyung Hong,6 Héctor Dueñas,7 Roberto Brugnoli8 1Eli Lilly and Company, Windlesham, Surrey, UK; 2Eli Lilly Australia Pty Ltd, West Ryde, NSW, Australia; 3Parc Sanitari Sant Joan de Déu, Fundació Sant Joan de Déu, CIBERSAM, Universitat de Barcelona, Barcelona, Spain; 4Department of Psychiatry, The First Affiliated Hospital of China Medical University, Shenyang, 5Lilly Suzhou Pharmaceutical Company, Ltd, Shanghai, People’s Republic of China; 6Department of Healthcare Management, Gachon University, Seongnam, South Korea; 7Eli Lilly de Mexico, Mexico City, Mexico; 8School of Medicine, Sapienza University of Rome, Rome, ItalyPurpose: To assess and compare the levels of functioning in patients with major depressive disorder treated with either duloxetine with a daily dose of ≤60 mg or a selective serotonin reuptake inhibitor (SSRI) as monotherapy for up to 6 months in a naturalistic setting in East Asia. In addition, this study examined the impact of painful physical symptoms (PPS) on the effects of these treatments.Patients and methods: Data for this post hoc analysis were taken from a 6-month prospective observational study involving 1,549 patients with major depressive disorder without sexual dysfunction. The present analysis focused on a subgroup of patients from East Asia (n=587). Functioning was measured using the Sheehan Disability Scale (SDS). Depression severity was assessed using the 16-item Quick Inventory of Depressive Symptomatology-Self Report. PPS were rated using the modified Somatic Symptom Inventory. A mixed model with repeated measures was fitted to compare the levels of functioning between duloxetine-treated (n=227) and SSRI-treated (n=225) patients, adjusting for baseline patient characteristics.Results: The mean SDS total score was similar between the two treatment cohorts (15.46 [standard deviation =6.11] in the duloxetine cohort and 16.36 [standard deviation =6.53] in the SSRI cohort, P=0.077) at baseline. Both descriptive and regression analyses confirmed improvement in functioning in both groups during follow-up, but duloxetine-treated patients achieved better functioning. At 24 weeks, the estimated mean SDS total score was 4.48 (standard error =0.80) in the duloxetine cohort, which was statistically significantly lower (ie, better functioning) than that of 6.76 (standard error =0.77) in the SSRI cohort (P<0.001). This treatment difference was more apparent in the subgroup of patients with PPS at baseline. Similar patterns were also observed for SDS subscores (work, social life, and family life).Conclusion: Depressed patients treated with duloxetine achieved better functioning compared to those treated with SSRIs. This treatment difference was mostly driven by patients with PPS at baseline.Keywords: depression, antidepressant, duloxetine, SSRI, functionin