Correlation between serum levels of interleukin-4 and alexithymia ...

Psychoneuroendocrinology 29 (2004) 686–691 www.elsevier.com/locate/psyneuen

Short Communication

Correlation between serum levels of interleukin4 and alexithymia scores in healthy female subjects: preliminary findings Maurice Corcos a,∗, Olivier Guilbaud a, Sabrina Paterniti a, Florence Curt a, Linnea Hjalmarsson a, Marle`ne Moussa b, Jean Chambry a, Gwenole´ Loas c, Ge´rard Chaouat b, Philippe Jeammet a a

c

Department of Psychiatry of Adolescents and Young Adults, Institut Mutualiste Montsouris, 42 Bd Jourdan, 75014 Paris, France b Inserm U 131, Hoˆpital Antoine Be´cle`re, 92140 Clamart, France Service Hospitalo-universitaire de psychiatrie, CHS, P. Pinel, route de Paris, Dury, 80044 Amiens, France Received 20 December 2002; received in revised form 21 March 2003; accepted 22 March 2003

Abstract Objective: Some studies suggest that inaccuracy in recognizing and describing emotional states, combined with a highly descriptive mode of expression, as in alexithymia, may influence the immune response. We therefore investigated in healthy women the relationship between alexithymia and circulating levels of IL-1, IL-2 and IL-4. Method: Seventeen mentally and physically healthy women aged between 20 and 25 years completed psychological questionnaires to assess alexithymia (Toronto Alexithymia Scale: TAS) and depressed mood (Hospital Anxiety and Depression Scale: HAD). Serum concentrations of IL-1, IL-2 and IL-4 were measured by ELISA. Results: We found a significant positive correlation between serum levels of IL-4 and TAS score (r = 0.55; p = 0.021) and between factor 1 of the TAS (difficulty in identifying feelings) and IL-4 (r = 0.57; p = 0.017) while serum IL-1 and IL-2 were not detected in ten and six patients, respectively. Although there was a significant correlation between age and IL-4 levels, a linear regression with BMI, age, depressed mood and TAS as independent variables showed that only alexithymia could predict significantly increased levels of IL-4.

∗

Corresponding author. Tel.: +33-(1)-5661-6919; fax: +33-(1)-5661-6918 E-mail address: [email protected] (M. Corcos).

0306-4530/$ - see front matter  2003 Elsevier Ltd. All rights reserved. doi:10.1016/S0306-4530(03)00087-8

M. Corcos et al. / Psychoneuroendocrinology 29 (2004) 686–691

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Conclusion: Alexithymia and difficulty in identifying feelings could be associated with increased levels of IL-4 which may result in chronic impairment of pro/anti-inflammatory cytokine balance with psychological and somatic consequences. Nevertheless, these intriguing findings would deserve replication and extension in a larger sample of subjects.  2003 Elsevier Ltd. All rights reserved. Keywords: Alexithymia; Interleukin 4; Cytokines

1. Introduction Alexithymia is a clinical construct described by Sifneos (1973) meaning no words for feelings. It is defined by a set of cognitive-affective deficits characterized by an inaccuracy in identifying and describing emotions; difficulty in distinguishing between feelings and the bodily sensations, paucity of daydreaming, fantasies and introspection; thought characterized by pragmatic content with a highly descriptive mode of expression. As the traditional psychosomatic paradigm, the alexithymia construct links the influence of emotions and personality on physical illness and health. Some studies suggest that inaccuracy in recognizing emotional states, or the way of coping with emotions, may influence immune function. However, little is known about the effects of alexithymia on immunity. It has been suggested that alexithymia is associated with impaired immune response. For instance, Todarello et al. (1994, 1997) found that alexithymic women had lower counts of almost all lymphocytic subsets compared to non-alexithymic women. Dewaraja et al. (1997) observed decreased cytotoxic lymphocyte counts (for the natural killer subset: CD57-CD16+ cells and killer effective T cell CD8+CD11a+cells) in highly alexithymic men compared to non-alexithymics. It has also been shown (Shea et al., 1993) that subjects classified as repressors of negative affect have lower immune responses than other groups of subjects. Lindholm et al. (1990) observed that alexithymia was associated with higher cortisol levels following dexamethasone administration, even after controlling for depression. This may be one possible neuroendocrine pathway associated with immune perturbation in alexithymic subjects. Thus immunological mechanisms may be involved in the pathophysiology of alexithymia. One reasonable approach to testing this hypothesis is the measurement of proinflammatory cytokines in body fluids, because cytokines such as IL-1, IL-2 are important mediators of interactions between the central nervous system (CNS) and the immune system. Moreover, the pro/anti-inflammatory balance needs to be studied. Indeed, deregulation of the anti-inflammatory cytokines such as IL-4 (a TH2 cytokine) may induce deregulation of the proinflammatory cytokine-induced immunological/inflammatory processes. To our knowledge, no study has focused on the relationship between alexithymia and cytokine production in healthy subjects. We therefore investigated in healthy women the relationship between alexithymia and circulating levels of IL-1, IL-2 (type 1 cytokine) and IL-4 (type 2 cytokine).

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2. Methods Women without psychiatric symptoms (evaluated by the Mini-International Neuropsychiatric Interview (M.I.N.I.) of Sheehan et al., 1998) and without current somatic disorders (as evaluated by medical report and examination) were recruited by means of announcements posted in nursing schools and in faculties of psychology and medicine in Paris. None of the subjects exhibited a major depressive episode (according to the M.I.N.I.). Seventeen women aged between 20 and 25 years were enrolled. All were second-year students or third-year nurses. They completed psychological questionnaires to assess alexithymia (Toronto Alexithymia Scale: TAS) and depressed mood (Hospital Anxiety and Depression Scale: HAD). They were excluded from the study if they had any inflammatory or autoimmune disease, acute or chronic organic diseases, if they recently had flu or a recent (within the past four weeks) history of an infectious disease, and if they had received any anti-inflammatory or immunosuppressive medication during the past four weeks. Subjects were tested in the follicular phase of their menstrual cycles, and none were receiving psychotropic treatments. All subjects provided written informed consent after explanation of the entire procedure. The protocol had been approved by the Consultative Committee for Protection of Persons involved in Biomedical Research (CCPPRB) of Paris-Hospital Cochin. 2.1. Assessment procedure All subjects completed a semi-structured diagnostic interview to identify the absence of psychiatric disorders, completed by a self-questionnaire eliciting psychological features, namely alexithymia and depressive mood (H.A.D scores). The absence of a current (or past) major depressive episode or other psychiatric disorder was assessed by means of the M.I.N.I. (Mini-International Neuropsychiatric Interview of Sheehan et al., 1998). Alexithymia was rated using the French translation of the revised Toronto Alexithymia Scale (Bagby et al., 1994; Loas et al., 1995) a self-report scale with 20 items. These items of the TAS are clustered into three factors: difficulties in identifying feelings (factor 1); difficulties describing feelings (factor 2); and externally orientated thinking (factor 3). Alexithymia was used as a continuous variable. After an overnight fast, blood samples were obtained by venipuncture from subjects between 0900 and 1000 h. After centrifugation of the blood at 4 °C, serum samples were separated, aliquoted and stored at ⫺20 °C until assayed. Enzymelinked immunosorbent assay (ELISA) kits were used to measure IL-1, IL-2 (R&D Systems, Quantikine, UK) and IL-4 (compact CLB, Tebu, France). The detection limits for IL-1, IL-2, IL-4 were under 1, 7 and 0.4 pg/ml, respectively. The intraassay coefficient of variation for IL-1, IL-2 and IL-4 assay were respectively under 3, 5 and 10%. The interassay coefficient of variation for IL-1, IL-2 and IL-4 assay were respectively under 5, 5 and 10%.


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2.2. Data analysis Data were analysed using SPSS 10 software. Serum levels of cytokines were log transformed to normalize the distribution. Geometric means and its confidence interval are given for cytokines. Pearson’s coefficient were used. Stepwise linear regression was used to assess the best model in predicting the levels of cytokines. The following variables were entered into the stepwise linear regression model as independent variables: alexithymia score, BMI, age, depressed mood (HAD). An a value of 0.05 was used to establish statistical significance for all analyses.

3. Results The mean ( ± standard deviation) age and BMI of the 17 subjects were respectively 22.82 ( ± 1.84) and 21.06 ( ± 1.92). The mean scores for alexithymia and depressed mood (HAD) were respectively of 41.94 ( ± 11.32) and 2.35 ( ± 2.08). In our sample, no significant correlation was observed between alexithymia and depressed mood (as evaluated by HAD). Only seven and 11 subjects had detectable serum IL-1 and IL-2 respectively, whereas all subjects had detectable serum IL-4. Considering the small number of subjects with detectable levels of IL-1 and IL-2, statistical analysis of our data was limited to serum levels of IL-4. Geometric mean of serum IL-4 and its confidence interval were 8.26 pg/ml [5.48; 12.45]. We found a significant positive correlation between serum levels of IL-4 and TAS score (r = 0.55; p = 0.021; see Fig. 1) and between IL-4 and factor 1 (difficulty in identifying feelings) of the TAS (r = 0.57; p = 0.017). With a model of stepwise linear regression analysis, serum levels of IL-4 were significantly linked with alexithymia but not with age or BMI or depressed mood (F = 6.03; b = 0.55; p = 0.021).

4. Discussion Our data show for the first time a statistically positive significant association between alexithymic features, notably its first dimension (difficulty in identifying feelings) and serum levels of IL-4. In terms of IL-4, this association was still noted after controlling for age, BMI and depressed mood. No significant correlation was found between HAD scores and TAS scores. This may be explained by the absence of clinical depression in our sample group of healthy subjects. Thus, the assessment of alexithymia may be more related to a primary dimension than to a situation-dependent phenomenon (state). In alexithymic subjects there may be an up-regulation of TH-2 cytokine production (IL-4).

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Fig. 1.

Correlation between alexithymia scores and serum IL-4 concentrations.

IL-4 is a modulator of key cytokines known to regulate the type 1/type 2 cytokine balance. Overproduction of IL-4 increases the TH2 response and notably the allergic response including IL-4 by inducing IgE antibody synthesis. It is unknown whether or not alexithymia is associated with the enhanced production of type 2 cytokines that contributes to the pathophysiology observed in allergic disease. According to some studies (Martin and Pihl, 1986; Rabavilas, 1987), alexithymic characteristics are related to sympathetic overreactivity. Iwakabe et al. (1998) found in experimental animals such as mice that stress may skew the TH1/TH2 balance toward TH2 dominant immunity, which stimulates the occurrence of infectious diseases and allergic disorders. According to Lindholm et al. (1990), alexithymic features may be connected with aberrant means of handling psychosocial stress. Due to their inability to identify and verbalise their emotions, alexithymics might present an exceptional stress reaction with poorly developed channels for proper emotional discharge. Lindholm et al. (1990) observed that alexithymia was associated with higher cortisol levels following Dexamethasone administration, even after controlling for depression. It is known that an increased production of glucocorticoid can promote type 2 cytokine production, notably IL-4 (Agarwal and Marshall, 2001). This might be responsible for impaired immune response or cytokine production. However, the limitations of our study should be borne in mind. We cannot specify immune function, since we only took into consideration serum concentrations of


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cytokines. These intriguing findings would deserve replication and extension in a larger sample of subjects. Further studies should assess several parameters under static and dynamic conditions (T and B lymphocyte number and subsets, production of TH-1 and TH-2 cytokines after mitogen stimulation of PBMC, IgE antibody production and eosinophil count). Investigation of the immunoendocrine system (especially the glucocorticoid axis) under stress conditions in alexithymic subjects may enhance understanding of the relationships between alexithymic features and the immune system. Further research is needed to validate these hypotheses and to cast light on any psychoneuroendocrine immunological pathway underlying alexithymia.

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