Psychosomatic Medicine 63:502-504 (2001)
© 2001 American Psychosomatic Society
Cytokines and Anorexia Nervosa
Maurice Corcos, MD,
Olivier Guilbaud, MD,
Gérard Chaouat, MD,
Véronique Cayol, MD,
Mario Speranza, MD,
Jean Chambry, MD,
Sabrina Paterniti, MD,
Marlène Moussa, MD,
Martine Flament, MD and
Philippe Jeammet, PhD
From the Department of Psychiatry Adolescent and Young Adult Psychiatry (Pr. Jeammet, Institute Mutualiste Montsouris) (M.C., M.S., J.C., M.F., P.J.) and Consultation Liaison Psychiatry Department (Pr. Consoli, Hôpital Européen Georges Pompidou) (O.G., S.P.), Paris; and INSERM U 131, Hôpital Antoine Beclere, Clamart (G.C., V.C., M.M.), Clamart, France.
Address reprint requests to: Dr. Maurice Corcos, Department of Adolescent and Young Adult Psychiatry, Institut Mutualiste Montsouris, 42 Bd Jourdan 75014 Paris, France. Email: maurice.corcos{at}imm.fr
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ABSTRACT
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OBJECTIVE: Recent studies have indicated that the inflammatory cytokines could be implicated in anorexia nervosa and in its complications. To determinate the potential role of interleukins (IL-1, IL-2, IL-4, IL-6, IL-10), interferon (IFN 
), tumor necrosis factor (TNF-
), and transforming growth factor (TGF-ß2) in anorexia nervosa, serum concentrations of these cytokines were measured in patients suffering from anorexia nervosa in comparison to healthy subjects.
METHOD: Twenty-nine anorexic women according to DSM-IV criteria participated in the study. The control group consisted of 20 healthy women without eating disorders, mood disorders, and immunological disorders.
RESULTS: We find that serum IL-2 and TGF-ß2 concentrations were both significantly decreased in anorexic patients, although the other cytokines did not differ significantly between the two groups.
CONCLUSION: Our results show that in patients with anorexia nervosa, there are lower levels of specific cytokines (especially IL-2 and TGF-ß2). These levels may reflect the combination of impaired nutrition and weight loss, therefore, the dysregulation of these cytokines may contribute in anorexia’s complications. Follow-up studies should examine the effects of parameters such as starvation, psychopathologic factors, and psychoneuroendocrinological perturbation which could affect interplay between cytokines, neuropeptides, and neurotransmitters.
Key Words: anorexia nervosa • cytokines • Interleukin 2, transforming growth factor.
Abbreviations: IFN- = interferon; IL = interleukins; CSF = colony-stimulating factors; ELISA = enzyme-linked immunosorbent assay technique; MIF = migration-inhibiting factors; LIF = leukemia-inhibiting factors; TNF- = tumor necrosis factor; TGF-ß2 = transforming growth factor; DSM-IV; Diagnostic and Statistical Manual of Mental Disorders, fourth edition; MANOVA = multivariate variance analysis
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INTRODUCTION
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Anorexia nervosa is a severe pathology of eating behaviors characterized by a weight loss leading to a body weight of less than 85% of the expected weight, amenorrhea and a distorted body image. Recent studies have shown the presence of immunological as well as endocrinological disturbances that seem to be closely related to the psychopathology of the disorder, thus creating a cycle of reciprocal influences that might be responsible for the perpetuation of the disorder. The complex interactions and reciprocal controls between the immune, the endocrine and the central nervous systems in anorexia nervosa are a major interest of the newly developed branch of psychoneuroimmunoendocrinology (1, 2). Different systems have been identified in this functional articulation including cerebral structures such as the rhinencephalon and the diencephalon, the autonomic nervous system as well as neuropeptides and lymphokines. It has been hypothesized that the immune system might be modulated by the endocrine and neurovegetative systems via certain neurohumoral mechanisms conveyed by neuropeptides (3). Specific abnormalities in central serotonin function have been implicated in the pathogenesis of anorexia nervosa (4). Moreover, alterations in serotoninergic central activity have been linked to modifications of the immune system. It has been shown that anorectic patients are relatively free from infectious diseases (5, 6). The immunological dysregulation in anorexia originates from several factors: the importance of undernourished states, the duration of the illness as well as the neuroendocrine and psychopathological status of the patients. Most of the studies exploring the immunological state of patients suffering from anorexia nervosa support the idea of an immunological suppression as well as a disturbance of the neuroendocrine system.
In a similar way, cytokines, glycoprotein factors serving as messengers between cells could be altered in anorexia nervosa. The spectrum of activity of these cytokines is particularly wide, including immunity, inflammation, infection, but also cell multiplication and hematopoiesis. Some cytokines have numerous immunological and metabolic activities and could also play a role as neurotransmitters (7). Various types of cytokines have been identified. The principal types of cytokines are growth factors (GF, or growth promoters), interleukins, interferons, TNF, and CSF; the other cytokines have not been divided into subgroups (MIF; LIF). Espat et al. (8) postulated that an increased and chronic production of cytokines such as TNF-, IFN-, IL-1, and IL-6 may favor the catabolic reactions and cachexy observed in cancerous states. Pathophysiological parallels have been made between the role of cytokines in cancerous cachexy and their putative involvement in the undernourished states observed in anorexia nervosa. TNF- and IL-6 are two proinflammatory cytokines that have been implicated as mediators of cancer-associated cachexia. Thus, in experimental animals peripherally and centrally secreted or injected IL-1, IL-6, and TNF- induce changes in neurochemical, behavioral, and physiological parameters, which have also been observed in anorexia nervosa (9). TNF-, which is known as cachexin, also mediates weight loss in rats. Recent studies have shown modifications of some cytokines in anorexia nervosa: Bessler et al. (10) found a decrease in the synthetic capacities of IL-1 and IL-2 in lymphocytic cells; Schattner et al. (11) has shown an increase in TNF- and a decrease of IFN- in lymphocyte production; Pommeroy et al. (12) found significantly increased IL-6 and TGF-ß serum rates, whereas Vaisman et al. (13) and Brambilla et al. (9) failed to find any modification in serum rates of IL-1, IL-3, IL-6, and TNF- in anorectic patients. In studies in which cytokine serum levels and/or cytokine lymphocyte synthetic activity were disturbed, a return to normal values was observed after renutrition.
Because of these controversial results, we evaluated which cytokines were elevated in serum in patients suffering from anorexia nervosa compared with a control group. The cytokines tested were IL-1, IL-2, IL-4, IL-6, IL-10, TNF-, TGF-ß2, and IFN-. The aim of this study was to determine whether the serum concentrations of these cytokines were altered in anorexia nervosa.
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MATERIALS AND METHODS
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The sample was selected from an eating disorders unit in Paris (Institute Montsouris Mutualist) within the framework of a multicentric research network called "COST," which evaluates the prognostic factors of eating disorders. Twenty-nine young anorectic women, aged 18 to 25 years, participated in the study. They were nonhospitalized female patients fulfilling the DSM-IV criteria for anorexia nervosa (14) and were compared with 20 "healthy" women. All patients and controls subjects were women. Average age of patients was 20.1 ±1.9 years compared with 23.7 ± 2.7 years for the control subjects. Controls and anorectic women were excluded from the study if they had any previous pregnancy, any inflammatory or autoimmune disease, or chronic organic diseases, if they had recently had flu, or if they were receiving any anti-inflammatory treatment. An additional exclusion criterion for controls was the presence of a personal or a family history of eating disorder or addictive behaviors or other psychiatric disorders (evaluated by MINI (15)). All subjects provided written informed consent before participation in the study.
Blood samples were obtained by venipuncture from patient and controls between 10 and 11 AM. The serum concentrations of cytokines were measured by ELISA, sandwich-type. These measures are based on specific monoclonal antibodies for each given cytokine. A panel of cytokines was tested, namely IL-1, IL-2, IL-4, IL-6, IL-10, TGF-ß, TNF-, and IFN-. Measurements were performed using commercial ELISA kits.
Statistical analyses were performed with the SPSS software 7.5 (SPSS Inc., Chicago, IL). The data are presented as mean ± SEM. MANOVA was first carried out by comparing the whole panel of cytokines (regarded as dependent variables) in patients and in controls. A Hotellings test was performed to assess the significance of the results, followed by a univariate F test for each cytokine in each sample.
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RESULTS
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A significant difference was found for the whole panel of cytokines tested between anorectic patients and the control group (MANOVA, Hotellings test: value = 0.44, N = 49; p = .047). This difference mainly is due to IL-2 and TGF-ß2 whose rates are significantly lower in anorectic patients compared with the normal controls (IL-2: F = 6.31; N = 49; p = .015; TGF-ß F = 5.79; N = 49; p = .02; cf Table 1). No differences were found between anorexics and controls concerning the other cytokines analyzed separately.
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DISCUSSION
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IL-2 and TGF-ß2 serum concentrations were significantly lower in patients with anorexia nervosa compared with the control group. In contrast to Vaisman et al. (13) and Brambilla et al. (9), we did not find any modification in the serum concentrations of IL-6, IL-1, TNF-, and IFN-. Holden and Pakula (16) have proposed a psychoneuroimmunological model of eating disorders in which a dysregulation of the immune system, involving certain cytokines (a rise in TNF- rates/a negative feedback of IL-2 and IL-4), could initiate a cascade of reactions and biochemical interactions that may result in either anorexia or bulimia nervosa. Our results suggest a limited role of these cytokines in anorexia, although we nevertheless found a decrease in IL-2 serum levels in anorexics. Studying the serum concentration of cytokines might not be the best way to investigate their relevance to the functioning of the central nervous system.
Several interpretations remain possible. Bessler et al. (10) has shown that a decrease in the synthetic activity of IL-2 mononuclear cells is reversible after renutrition. Malnutrition would thus be responsible for the immunological dysregulation of this cytokine. Concerning our study, we measured IL-2 serum concentrations and not the synthetic activity of the white cells (mononuclears). We did not find any study in the literature concerning IL-2 serum levels, except for soluble IL-2 receptor. Nagata et al. (17) found a significantly lower ratio of soluble IL-2 receptor in patients with restrictive-type anorexia, and Polack and Nahmod (18) found no differences.
An analysis of the results in terms of circulating levels of IL-2 remains complex; this cytokine comes primarily from four principal sources of synthesis: the intestinal mucous membrane, the immune system (white blood cells), the central nervous system, and also from the adipocytes. It is possible that lowered levels could be mainly related to a deficiency of nutritional supplies as well as to the atrophy or the alteration of the intestinal mucous membrane due to prolonged starvation and to the associated malnutrition. Comparing the profile of anorexic patients to recovered anorexics might better help to disentangle the effect of weight on IL-2 dysregulation. It would require cross-sectional and longitudinal studies evaluating IL-2 circulating levels in anorectic patients before and after renutrition by taking into account parameters such as depression and the concentration of certain neurotransmitters. As far as TGF-ß2 is concerned, our study did not confirm the results of Pommeroy et al. (12) who showed a significant serum increase for this cytokine in a sample of 16 patients with anorexia nervosa.
From our study, we cannot elucidate the role of the immune system in anorexia nervosa, inasmuch as our research only considered the serum concentrations of these cytokines. Future studies should include a multifactorial pattern that considers the combination of impaired nutrition, chronic stress, and depression as well as endocrine and neurotransmitter dysregulation. To clarify the dysregulation of TGF-ß2 and IL-2 in anorexia nervosa, longitudinal studies are needed to assess their impact and role in eating disorders.
Received for publication August 10, 1999.
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ABSTRACT
INTRODUCTION
