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Original Studies |
(TNF-) and Soluble TNF Receptors in Patients with Anorexia Nervosa1
College of Medical Technology (Y.N.) and Department of Psychiatry (S.H.) Kyoto University, Kyoto 606-8507; Takagi Psychiatric Clinic (R.T.), Kyoto 606-8507; Kansai-Denryoku-Hospital (A.T.), Osaka 553-0003; and Mitsubishi Kagaku Bio-Clinical Laboratory Inc. (F.K.), Tokyo 174-0056, Japan
Address all correspondence and requests for reprints to: Yoshikatsu Nakai, M.D., College of Medical Technology, Kyoto University, 53 Kawaharacho, Shogoin, Sakyo-ku, Kyoto, 606-8507, Japan. E-mail: YN{at}itan.kyoto-u.ac.jp
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Abstract |
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 Top Abstract IntroductionSubjects and MethodsResultsDiscussionReferences |
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(TNF-) is a cytokine with numerous
immunological and metabolic activities. To study the role of TNF- on
the pathophysiology of anorexia nervosa and its complications, plasma
concentrations of TNF-, 2 soluble TNF receptors (sTNF-RI and
sTNF-RII), and leptin were measured in 20 female patients with anorexia
nervosa (AN) and 20 age-matched normal women (N). Plasma TNF-
concentrations in AN were significantly higher than those in N
(4.1 ± 0.6 pg/mL vs. 1.6 ± 0.1 pg/mL;
P < 0.01). Although no significant difference was
observed in plasma sTNF-RI concentrations between the two groups,
plasma sTNF-RII concentrations in AN were significantly higher than
those in N (2094.0 ± 138.5 pg/mL vs. 1569.5 ±
84.0 pg/mL; P < 0.01). Plasma concentrations of
TNF- and sTNF-RII after treatment of 8 anorectic patients were not
different from those before treatment, although body fat mass and
plasma leptin concentrations significantly increased after treatment.
Plasma TNF- concentrations were not related to body fat mass in
anorectic patients. These results suggest that the adipose tissue may
not be the immediate source of TNF- in anorectic patients and that
TNF- may contribute to the pathophysiology of immunological and
metabolic abnormalities in anorexia nervosa. . |
Introduction |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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Tumor necrosis factor- (TNF-), also known as cachectin, is
a cytokine with numerous immunological and metabolic activities. Of
particular interest is its ability to mediate weight loss in
experimental animals by several mechanisms including suppression of
food intake, suppression of lipoprotein lipase, and catabolic effects
on energy storage tissues (7). However, the effect of TNF- in
mediating cachexia in cancer and in chronic infections in humans has
not yet been unequivocally demonstrated (8, 9). Using available assays,
number of papers were published concerning the lack of reliability of
TNF- measurements in plasma and the relationship of bioassay to
immunoassay (7, 9).
There are two TNF- receptors: TNF-RI (55kDa) and TNF-RII
(75kDa) (10). Soluble forms of the two TNF- receptors (sTNF-RI and
sTNF-RII), which represent the extracellular portions of
membrane-associated TNF- receptors, have been identified in serum
and urine and play a role as modulators of the biological function of
TNF- in an agonist/antagonist pattern (11). Because injection of
TNF- results in increased shedding of TNF- receptors, it is
likely that TNF- release is reflected by sTNF-R levels (12). The
measurement of sTNF-R may therefore be critically important, not
only with respect to the validity of the particular assay used, but in
the interpretation of accompanying TNF- levels (9).
Schattner et al. (13) found increased spontaneous
production of TNF- in vitro by peripheral blood
mononuclear cells from patients with anorexia nervosa. However, TNF-
production after stimulation of peripheral blood mononuclear cells by
phytohemagglutinin was not different from controls. Furthermore,
spontaneous TNF- production in vitro was in the normal
range in the chronically undernourished subjects (14). There were only
two reports, to our knowledge, that plasma TNF- concentrations were
measured in anorexia nervosa. Plasma TNF- was not detected in both
anorectic patients and control subjects in these reports (13, 15).
There was no report about plasma sTNF-R concentrations in anorexia
nervosa.
Based on the above, it is natural to question whether the
anorectic patients have a higher-than-normal concentrations of TNF-
and sTNF-R in plasma, and TNF- may play some role in the
pathophysiology of anorexia nervosa and its complications. In the
present study, therefore, we measured plasma concentrations of TNF-,
sTNF-RI, and sTNF-RII with sensitive assays in female patients with
anorexia nervosa and in normal control women.
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Subjects and Methods |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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The study subjects were 20 female patients with anorexia nervosa and 20 healthy women. All the untreated anorectic patients who visited our clinic were used for the study except those who had concurrently bulimia nervosa. A diagnosis of anorexia nervosa and bulimia nervosa was made according to the criteria of DSM-IV (1). The duration of the illness was 45.0 ± 9.6 (mean ± SEM) months. Eight of 20 anorectic patients were restudied after achievement of goal body mass index (BMI) (more than 18.0 kg/m2). All patients were treated with cognitive-behavioral approach. The duration of the treatment was 7.4 ± 1.2 months. Control subjects were age-matched healthy women whose BMI was in the range of 18.0–22.0 kg/m2. All anorectic patients before and after the treatment with amenorrheic, and controls were studied in the follicular phase of the menstrual cycle. None of them had any associated illness, nor were they receiving any medications when studied. There were no infectious complications throughout the study. All gave their informed consent for the study.
Methods
A blood sample was collected from each subject while fasting,
and plasma was frozen until analysis. Plasma TNF- concentrations
were measured by enzyme immunoassay kit (Quantikine HS Human TNF-
immunoassay kit, R & D Systems, Inc, Minneapolis, MN). The limit of
sensitivity was 0.50 pg/mL, the intraassay coefficient of variation was
6.3%, and the interassay coefficient of variation was 7.6%. Plasma
concentrations of sTNF-RI and sTNF-RII were measured by enzyme-linked
immunosorbent assay (ELISA) (BIOTRAK, Amersham Life Science, Uppsala,
Sweden). The limits of sensitivity for sTNF-RI and sTNF-RII were 25
pg/mL and 50 pg/mL, respectively. Intraassay coefficient of variation
and interassay coefficient of variation for both assays were less than
5% and less than 7%, respectively. Plasma leptin concentrations were
measured by RIA using commercial kits (Human Leptin RIA kit, Linco
Research Inc., St. Charles, MO). The limit of sensitivity was 0.5
ng/mL, the intraassay coefficient of variation was 3.5%, and the
interassay coefficient of variation was 2.3%. Body fat mass was
determined by multiplying the percent of body fat by the body weight.
The percent of body fat was determined from bioelectric impedance
analysis, a method that has been validated (16).
Results are expressed as mean ± SEM. The
significance of difference was tested with Student’s t test
for paired or unpaired data, with the level of statistical significance
at P < 0.05. Plasma concentrations of leptin and
TNF- were log transformed to normalize the distribution,
respectively. Linear regression analysis was used to assess the degree
of association between various indices. All calculations were performed
using Statview version 4.5 (Abacus Concepts Inc., Berkley, CA).
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Results |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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Results in plasma concentrations of TNF-, sTNF-RI, sTNF-RII,
and leptin in 20 normal controls and 20 anorectic patients are depicted
in Fig. 1
. Plasma TNF- concentrations
were significantly higher in 20 anorectic patients than in 20 controls
(4.1 ± 0.6 pg/mL vs. 1.6 ± 0.1 pg/mL;
P < 0.01). No significant difference was observed in
plasma sTNF-RI concentrations between the two groups (566.9 ±
45.3 pg/mL vs. 611.6 ± 26.6 pg/mL). Plasma sTNF-RII
concentrations were significantly higher in anorectic patients than in
controls (2094.0 ± 138.5 pg/mL vs. 1569.5 ± 84.0
pg/mL; P < 0.01). Plasma leptin concentrations were
significantly lower in anorectic patients than in controls (1.7 ±
0.1 ng/mL vs. 6.5 ± 0.5 ng/mL; P <
0.01). Plasma leptin concentrations were significantly related to body
fat mass (r = 0.805, P < 0.01) or to BMI (r
= 0.780, P < 0.01) in anorectic patients. However,
plasma concentrations of TNF-, sTNF-RI, and sTNF-RII were not
related to plasma leptin concentrations or to body fat mass in these
patients, respectively.
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concentrations after were not
significantly different from those before the treatment (4.5 ±
0.7 pg/mL vs. 4.1 ± 0.8 pg/mL). Plasma sTNF-RII
concentrations after were not significantly different from those before
the treatment (1945.0 ± 152.2 pg/mL vs. 1940.0 ±
190.6 pg/mL) (Fig. 2).
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Discussion |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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concentrations were significantly higher in anorectic patients than in
normal controls (Fig. 1
). Our present results are consonant with the
previous findings by Schattner et al. (13) that anorectic patients had
increased spontaneous production of TNF- by peripheral blood
mononuclear cells in vitro. TNF- is mainly produced by
stimulated monocytes, macrophages, and T-lymphocyte subsets in response
to bacterial toxines, inflammatory products, and other invasive stimuli
(7). It has recently been demonstrated that TNF- is constitutively
expressed by adipose tissue (17). Obesity is associated with increased
plasma TNF- concentrations (18), and TNF- may be a mediator of
insulin resistance (17). We have no direct evidence for the source of
plasma TNF- in anorectic patients. However, the adipose tissue may
not be the immediate source of TNF- in these patients, because
plasma TNF- concentrations are not related to body fat mass.
Furthermore, plasma TNF- concentrations after treatment were
not significantly different from those before treatment in 8 anorectic
patients, although body fat mass and plasma leptin concentrations were
significantly increased after the treatment in these patients (Fig. 2).
After successful nutritional repletion in anorectic patients, the
changes in cell-mediated cytotoxicity and TNF- production in
vitro were reversed in the studies by Vaisman et al.
(14, 19). The discrepancy between the studies by Vaisman et
al. and ours may be attributable to the different methods;
in vitro vs. in vivo (20).
The biological and metabolic effects of TNF- have been
studied. In general, acute exposure to high doses of TNF- results in
shock and tissue injury virtually indistinguishable from septic shock
syndrome. On the other hand, chronic TNF-exposure causes the
development of cachexia characterized by anorexia, weight loss, and
depletion of whole-body protein and lipid (7). Therefore, our present
findings suggest that TNF- may play some role for the metabolic
abnormalities in anorectic patients.
Meanwhile, TNF- is a pivotal mediator of inflammation that
activates leukocytes, enhances adherence of neutrophils and monocytes
to endothelium, promotes migration of inflammatory cells into the
intercellular matrix, and triggers local production of other
proinflammatory cytokines (7). Furthermore, the experiments with mice
deficient in TNF- suggest that TNF- is a potent anti-inflammatory
cytokine (21, 22). These cytokines have been implicated in the
beneficial effects of TNF-; TNF- may modify the impaired immune
function in anorectic patients (3, 13).
In the present study plasma concentrations of sTNF-RII in
anorectic patients were significantly higher than those in normal
controls, whereas no significant difference was observed in plasma
sTNF-RI concentrations between the two groups (Fig. 1). A variety of
stimuli trigger the shedding of sTNF-R from the cell surface into the
circulation through proteolytic processing (11). Available evidence
suggests that plasma sTNF-R concentrations are a sensitive indicator of
activation of the TNF- system (9, 11, 12). The majority of
biological responses classically attributed to TNF- are mediated by
TNF-RI. However, the recent studies using mice lacking one or both TNF
receptors suggest a dominant role of TNF-RII in suppressing
TNF-mediated inflammatory responses (23). To elucidate the significance
of the elevated plasma sTNF-RII concentrations in anorectic patients,
further investigation is needed.
In summary, plasma concentrations of TNF- and sTNF-RII are
significantly higher in anorectic patients than in normal controls.
These concentrations remain altered in anorectic patients even after
weight restoration. Plasma TNF- concentrations were not related to
body fat mass in anorectic patients. These results suggest that the
adipose tissue may not be the immediate source of TNF- in anorectic
patients and that TNF- may contribute to the pathophysiology of
immunological and metabolic abnormalities in anorexia nervosa.
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Acknowledgments |
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Footnotes |
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Received September 15, 1998.
Revised December 17, 1998.
Accepted January 4, 1999.
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References |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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and anorexia—cause or effect? Metabolism. 40:720–723.[CrossRef][Medline]
: direct role in
obesity-linked insulin resistance. Science. 259:87–91. in sera of
obese patients: fall with weight loss. J Clin Endocrinol Metab. 83:2907–2910.
production decreased after a 5-km run? Eur J Clin Invest. 28:873–874.[CrossRef][Medline]
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