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Background: Recently, hypothalamus-pituitary-adrenal (HPA) axis function assessed with the combined dexamethasone (DEX)/corticotropin releasing hormone (CRH) test has been shown to be associated with response to antidepressant treatment. A polymorphism (rs16944) in the interleukin-1beta (IL-1b) gene has also been reported to be associated with the medication response in depression. These findings prompted us to examine the possible association between IL-1b gene polymorphisms and HPA axis function assessed with the DEX/CRH test. Methods: DEX/CRH test was performed in 179 healthy volunteers (45 males: mean age 40.5 ± 15.8 years; 134 females: mean age 47.1 ± 13.2 years). Five tagging single nucleotide polymorphisms (SNPs) of IL-1b gene (rs2853550, rs1143634, rs1143633, rs1143630, rs16944) were selected at an r threshold of 0.80 with a minor allele frequency > 0.1. Genotyping was performed by the TaqMan allelic discrimination assay. A two-way factorial analysis of variance (ANOVA) was performed with the DEX/CRH test results as the dependent variable and genotype and gender as independent variables. To account for multiple testing, P values < 0.01 were considered statistically significant for associations between the genotypes and the cortisol levels. Results: The cortisol levels after DEX administration (DST-Cortisol) showed significant associations with the genotypes of rs16944 (P = 0.00049) and rs1143633 (P = 0.0060), with no significant gender effect or genotype × gender interaction. On the other hand, cortisol levels after CRH administration (DEX/CRH-Cortisol) were affected by gender but were not significantly influenced by the genotype of the examined SNPs, with no significant genotype × gender interaction. Conclusions: Our results suggest that genetic variations in the IL-1b gene contribute to the HPA axis alteration assessed by DST-Cortisol in healthy subjects. On the other hand, no significant associations of the IL-1b gene polymorphisms with the DEX/CRH-Cortisol were observed. Confirmation of our findings in futures studies may add new insight into the communication between the immune system and the HPA axis. Background [4,5]. In experimental animals, exogenous administra- Recent studies have provided several lines of evidence tions of IL-1b have produced depressive-like symptoms, implicating the pro-inflammatory cytokine interleukin- which were attenuated by treatment with antidepres- 1beta (IL-1b) in the etiology and pathophysiology of sants [6,7]. Furthermore, administration of the IL-1 depression. Studies investigating peripheral levels of IL- receptor antagonist has ameliorated the stress-like 1b have reported elevated concentrations of IL-1b in effects in cellular and behavioral models [8,9], making it patients with major depression [1-3] and dysthymia a possible candidate for therapeutic targets. A few studies have examined genetic polymorphisms * Correspondence: email@example.com of the IL-1b gene for association with depression. Department of Mental Disorder Research, National Institute of Neuroscience, Although no significant allelic or genotypic differences National Center of Neurology and Psychiatry, Kodaira, Tokyo, 187-8502, have been found between patients with depression and Japan Full list of author information is available at the end of the article © 2011 Sasayama et al; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Sasayama et al. Behavioral and Brain Functions 2011, 7:23 Page 2 of 8 http://www.behavioralandbrainfunctions.com/content/7/1/23 healthy controls [10-12], three studies have consistently Because gender effects on measures of HPA axis func- shown that the G allele of rs16944 in the IL-1b gene is tion have been previously reported [32,35], a two-way associated with poor response to antidepressant factorial analysis of variance (ANOVA) was performed treatment [10,13,14]. This evidence suggests that genetic with the DEX/CRH test results as the dependent vari- regulation of inflammatory processes mediated by IL-1b able and genotype and gender as independent variables is involved in the pathophysiology of depression and to determine the possible interaction effects between the resistance to antidepressant treatment. polymorphisms and gender. Alterations in the hypothalamic-pituitary-adrenal (HPA) axis have been well-documented in depression Methods and related psychopathological conditions (reviewed by Subjects [15,16]). We have also reported heightened HPA axis in Subjects were 179 adult healthy volunteers (45 males: major depression and its normalization after treatment mean age 40.5 ± 15.8 years, 134 females: mean age 47.1 as assessed with the combined dexamethasone (DEX)/ ± 13.2 years) recruited from the community through corticotropin releasing hormone (CRH) test [17,18]. The advertisements in free local information magazines and relationship between alteration of the HPA axis activa- by our website announcement. Most of the subjects tion and immune alterations in depression has been were from our previous sample, in which the relation- described in several studies [19-21]. The increased ship between stress, sleep, and HPA function was exam- expression of pro-inflammatory cytokines is thought to ined [36-38]. All subjects were biologically unrelated lead to the progression of the immune response and Japanese individuals without current or past history of activation of the HPA axis [22-24]. In particular, IL-1b psychiatric treatment, and were screened with a direct is considered to play an important role in the HPA axis contact interview by a research psychiatrist using the alteration. A significant positive correlation between Japanese version of the Mini International Neuropsy- mitogen-induced IL-1b production and post-DEX corti- chiatric Interview (M.I.N.I.) [39,40] to rule out any axis sol values have been reported, suggesting that IL-1b I psychiatric disorders. Participants were excluded if hypersecretion may contribute to HPA axis hyperactivity they had prior medical histories of central nervous . Animal studies have further demonstrated that the system disease or severe head injury, if they met the cri- release of CRH stimulated by IL-1 is involved in the teria for substance abuse or dependence or mental retar- HPA activation [26-28]. dation, if they had received glucocorticoid treatment, Intriguingly, a number of studies have shown that the psychotropic treatment, antihypertensive medications, DEX/CRH test may be a predictor for response to oral contraceptives, or estrogen replacement therapies in antidepressant treatment. Ising et al  found that the previous month, or if they suffered from any inflam- higher cortisol level after DEX administration prior to matory, infectious, or systemic immune diseases, based CRH stimulation was associated with a favorable treat- on self-reports, at the time of assessment. The study ment outcome. Two recent studies showed that protocol was approved by the ethics committee at the response to antidepressant treatment was more favor- National Center of Neurology and Psychiatry, Japan. able in depressive patients whose peak cortisol levels After description of the study, written informed consent during the DEX/CRH test were reduced after the initia- was obtained from every subject. tion of the treatment [30,31]. Further, in the study by Binder et al , antidepressant response was associated Genotyping with higher cortisol response to the DEX/CRH test in Five tagging single nucleotide polymorphisms (SNPs) in male, but not female, patients. It is plausible that the a region 1 kilobase (kb) upstream to 1 kb downstream DEX/CRH test and the antidepressant response are of the IL-1b gene (rs2853550, rs1143634, rs1143633, related, since antidepressants may exert their clinical rs1143630, rs16944) were selected by Haploview 4.2  effects, at least in part, by reducing the activity of the using Japanese and Chinese population in the HapMap HPAsystem[33,34]. Thefactthatboththe HPAaxis SNP set (release 22), at an r thresholdof0.80with a activity and the IL-1b gene polymorphism influence the minor allele frequency greater than 0.1. Genomic response to antidepressants further supports the organization and linkage disequilibrium structure of the evidence of reciprocal relationships between the HPA IL-1b gene are shown in Figure 1. Genomic DNA was system and IL-1b. prepared from the venous blood according to standard These previous findings prompted us to examine the procedures. The SNPs were genotyped using the Taq- possible association of polymorphisms in the IL-1b and Man 5’-exonuclease allelic discrimination assay. Thermal the HPA function. In the present study, the relationship cycling conditions for polymerase chain reaction were 1 between the IL-1b gene polymorphisms and the results cycle at 95°C for 10 minutes followed by 50 cycles of of the DEX/CRH test was examined in healthy subjects. 92°C for 15 seconds and 60°C for 1 minute. The Sasayama et al. Behavioral and Brain Functions 2011, 7:23 Page 3 of 8 http://www.behavioralandbrainfunctions.com/content/7/1/23 a. SNPs in the promoter region b. Intronic SNPs c. Synonymous SNPs Figure 1 Genomic organization and LD structure of the IL-1b gene. Genomic organization and linkage disequilibrium (LD) structure of the IL-1b gene are shown. Exons are shown as boxes. Shades of pink represent extent of LD (red denotes D’ = 1). Numbers in squares give r values multiplied by 100. The names of the examined SNPs are enclosed in boxes. allele-specific fluorescence was measured with ABI rested semi-supine throughout the testing. Blood samples PRISM 7900 Sequence Detection Systems (Applied Bio- were immediately centrifuged and stored at -20°C. systems, Foster city, CA, USA). Genotype data were Plasma concentrations of cortisol were measured by read blind to the DEX/CRH test results. Ambiguous radioimmunoassay at SRL Corporation (Tokyo, Japan). genotype data were not included in the analysis. The detection limit for cortisol was 1.0 μg/dl. Cortisol values under the detection limit were treated as 0 μg/dl. DEX/CRH test The intra-assay coefficients of variation at 2.37 μg/dl, The DEX/CRH test was administered according to a pro- 13.02 μg/dl, and 36.73 μg/dl were 6.90%, 4.94%, and tocol proposed in a previous report , which was also 5.78%, respectively. The inter-assay coefficients of varia- employed in our recent report . The subjects were tion at 2.55 μg/dl, 13.04 μg/dl, and 34.17 μg/dl were administered 1.5 mg of DEX (Banyu Pharmaceutical Cor- 8.91%, 6.03%, and 6.44%, respectively (SRL Corporation, poration, Tokyo, Japan) orally at 23.00 h. On the next Tokyo, Japan). Outcome measures of this neuroendo- day, they attended our laboratory and sat on a comforta- crine test were the DST-Cortisol (i.e., the concentration ble couch in a calm room. A vein was cannulated at of cortisol [μg/dl]at15.00 h)andDEX/CRH-Cortisol 14.30 h to collect blood samples at 15.00 and 16.00 h via (i.e., the concentration of cortisol at 16.00 h). an intravenous catheter. Human CRH (100 μg) (hCRH ‘Mitsubishi’, Mitsubishi Pharma Corporation, Tokyo, Statistical analysis Japan) was administered intravenously at 15.00 h, imme- Deviations of genotype distributions from Hardy-Wein- diately after the first blood collection. Subjects fasted and berg equilibrium (HWE) were assessed using the c test Sasayama et al. Behavioral and Brain Functions 2011, 7:23 Page 4 of 8 http://www.behavioralandbrainfunctions.com/content/7/1/23 for goodness of fit. To determine the interaction effects with DST-Cortisol or DEX/CRH-Cortisol in either between genotype and gender, two-way factorial analysis gender (all P > 0.05). of variance (ANOVA) was performed with the trans- Additional file 1 (Table S1) presents the results of the formed cortisol levels as the dependent variable and two-way ANOVA performed with the transformed genotype and gender as independent variables. Because plasma cortisol levels as the dependent variable and gen- the cortisol levels were not normally distributed, the otype and gender as independent variables. Significant aligned rank transformation method was used to trans- effects of genotype on DST-Cortisol were observed for form the data prior to conducting ANOVA . To rs1143633 and rs16944, with no significant gender effect correct for the multiple comparisons, statistical signifi- or genotype × gender interaction. The means of the cance was set at two-tailed P < 0.01 when the analysis DST-Cortisol in each genotype of rs1143633 and was performed for each of the 5 SNPs. Otherwise, statis- rs16944 and the significance levels of Tukey’s post hoc tical significance was set at two-tailed P < 0.05. Analyses tests are shown in Figure 2. Regarding DEX/CRH-Corti- were performed using the Statistical Package for the sol, significant gender effects were demonstrated in Social Sciences (SPSS) version 11.0 (SPSS Japan, Tokyo). three of the two-way ANOVA results. No significant genotype effect or genotype × gender interaction was Results observed for DEX/CRH-Cortisol. None of the examined SNPs deviated significantly from HWE after Bonferroni correction (all P >0.01), Discussion although rs1143633 showed a trend towards excess of To our knowledge, this is the first study that revealed heterozygotes over Hardy-Weinberg expectations (c = thepossiblerole of IL-1b polymorphisms on HPA axis 6.48, P < 0.05). Age showed no significant correlation function. Two studies have reported the influence of Figure 2 Mean DST-Cortisol levels. The means of the DST-Cortisol levels in each genotype of rs1143633 (Figure 2a) and rs16944 (Figure 2b) are shown. Error bars indicate the standard errors of the means. Asterisks in the graph indicate significance levels of the Tukey’s post hoc test. * P < 0.01, ** P < 0.001, *** P < 0.0001. Sasayama et al. Behavioral and Brain Functions 2011, 7:23 Page 5 of 8 http://www.behavioralandbrainfunctions.com/content/7/1/23 genetic polymorphisms on DEX suppression test (DST) furtherstudy with alargersamplesizemay be [43,44], one of which has shown that an allele in a poly- warranted. morphism within the CRHBP gene, which regulates the The findings on biological roles of rs16944 poly- CRH system, was associated with pronounced DEX sup- morphism have not been consistent across studies. A/A pression of corticotropin and with nonresponse to cita- genotype has been associated with higher gastric mucosa lopram treatment in depressed subjects . Some IL-1b levels in H. pylori positive population . On the studies have also reported the influence of genetic poly- other hand, mononuclear cells from subjects with G/G morphisms on DEX/CRH-Cortisol. Schule et al  genotype showed an increased release of IL-1b after sti- reported that brain-derived neurotrophic factor Val66- mulation with lipopolysaccharide . Recent studies Met polymorphism is associated with HPA axis activity suggest that the functional role of rs16944 may depend during the DEX/CRH test in depressed patients. There on the IL-1b promoter region haplotypes including is also a study reporting an association of a polymorph- rs16944 and rs1143627 [51-54]. Although the findings ism of the preprogalanin gene with DEX/CRH test are inconsistent, these previous studies suggest that results and antidepressant treatment response . Our rs16944 could affect the expression levels of IL-1b.The study adds to accumulating evidence that genetic factors biological role of rs1143633, on the other hand, has not could influence the activity of the HPA axis. been previously reported. Previous studies have shown associations of HPA Previous studies showed that administration of DEX axis activity assessed by the DEX/CRH test with anti- inhibited lipopolysaccharide (LPS)-stiumulated produc- depressant treatment [30-32].Furthermore,higher cor- tion of IL-1b [55,56], suggesting that DEX may affect tisol level after DEX administration prior to CRH the function of IL-1b gene.Therefore,futurestudies stimulation was also associated with a favorable treat- should examine the influence of IL-1b gene polymorph- ment outcome . Since the IL-1b gene polymorph- isms on not only basal IL-1b levels but also DEX- ism is also known to influence the response to induced IL-1b levels. The decrease of the LPS-induced antidepressants, we expected that association between IL-1b gene expression by DEX may be caused by the IL-1b gene and HPA activity assessed by the DEX/ inhibition of nuclear factor binding to the IL-1b gene CRH test would be found. However, our results promoter . It is noteworthy that, in the present showed that only DST-Cortisol, but not DEX/CRH- study, the HPA response to DEX was affected by Cortisol, was significantly associated with the IL-1b rs16944, which is located in the promoter region of the gene polymorphisms. Thus, the relationship of the IL-1b gene. HPA activity and the IL-1b gene polymorphism with The following limitations must be considered when the antidepressant response could not be fully interpreting the results. First, since the DEX/CRH test explained from our findings. Although the present used here was based on a simple test protocol, we could study was performed in healthy subjects, it is possible notcalculate thecortisolareaunder thecurve [57,58]. that a different regulatory mechanism of HPA axis We also did not measure the adrenocorticotropic hor- which overweighs the effect of the polymorphisms mone levels, which was measured in previous studies to examined in the present study may exist in depressive determine the pituitary glucocorticoid negative feedback patients. Further studies must be carried out to deter- [30,45,57-59]. Moreover, we did not measure the base- mine HPA axis regulation in patients with depression. line levels of cortisol. The extent to which the cortisol Significant gender effects were observed for DEX/ was suppressed in response to DEX administration CRH-Cortisol, consistent with previous studies [18,47]. could not be determined from our data. There may have However, as mentioned above, the DEX/CRH-Cortisol been a genotype dependent alteration of the baseline did not show significant associations with any of the cortisol levels, which appeared in the present study as a SNPs examined. This may partly be explained by the genotype effect on DST-Cortisol. This will need further putative action of IL-1b on hypothalamus. Animal stu- investigation. We also did not perform physical exami- dies have shown that IL-1b is involved in the noradrena- nation to rule out physical disorders. As the presence or line-induced release of CRH from the hypothalamus absence of inflammatory and immune diseases were [28,48]. Therefore, higher IL-1b expression in the brain basedonlyonself-reports, theresults mayhavebeen may facilitate the release of CRH even when the sup- affected by unrecognized inflammatory processes in pressive effect of DEX is exerted, resulting in higher some participants. Furthermore, the lack of data on DST-Cortisol. On the other hand, the effect of IL-1b on menstrual cycle or menopausal status in the female par- the DEX/CRH-Cortisol could be small if the administra- ticipants may have also influenced the results. Another tion of CRH overweighs the effect of IL-1b expression limitation of the study is that we did not assess the bio- level. Because rs1143634 and rs1143633 showed a trend logical role of IL-1b polymorphisms. The association of towards association with DEX/CRH-Cortisol (P <0.1), a IL-1b expression level with the IL-1b polymorphisms Sasayama et al. Behavioral and Brain Functions 2011, 7:23 Page 6 of 8 http://www.behavioralandbrainfunctions.com/content/7/1/23 References needs to be investigated in the future. Finally, the pre- 1. Owen BM, Eccleston D, Ferrier IN, Young AH: Raised levels of plasma sent study included only healthy subjects. Whether the interleukin-1beta in major and postviral depression. 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Behavioral and Brain Functions – Springer Journals
Published: Jul 5, 2011
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