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1 Third Department of Internal Medicine and 2 Department of Anatomy and Neurobiology, Kyoto Prefectural University of Medicine, Kawaramachi-Hirokoji, Kamigyo-ku, Kyoto 602-0841, Japan
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ABSTRACT |
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 TOP
 ABSTRACT
 INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
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We investigated the responses of the hypothalamic-pituitary-adrenal (HPA) axis during experimental colitis induced by intracolonic administration of 2,4,6-trinitrobenzenesulfonic acid in the rat. On days 3 and 7 after induction of colitis, the corticotropin-releasing hormone (CRH) mRNA level in the parvocellular paraventricular nucleus (pPVN) of the hypothalamus was reduced, the plasma ACTH level remained at the basal level, and the plasma corticosterone (Cort) level was high. Induction of colitis on day 3 after adrenalectomy with Cort pellet replacement (ADX + Cort) resulted in a marked increase in CRH mRNA on day 7 after induction of colitis compared with noncolitic ADX + Cort animals. Pair feeding to match the food intake of the colitic animals resulted in no significant change in CRH mRNA in the pPVN, plasma ACTH, and Cort compared with healthy control animals. These findings indicated that CRH mRNA expression in the pPVN was inhibited by glucocorticoid feedback during this experimental colitis, and the decrease in food intake during colitis was not simply responsible for the expression of CRH mRNA. It is inferred that the HPA axis including the CRH level in the pPVN is altered in patients with inflammatory bowel disease.
corticotropin-releasing hormone; adrenocorticotropic hormone; corticosterone; adrenalectomy; 2,4,6-trinitrobenzenesulfonic acid
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INTRODUCTION |
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TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
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INFLAMMATORY BOWEL DISEASE (IBD) is a chronic condition characterized by an unpredictable clinical course with periods of remission and relapse of variable durations (12), and the role of stressors in the modulation of disease activity in IBD is gaining recognition (27). There is evidence that the central nervous system activated by stressors may amplify or modulate aspects of intestinal inflammation through alterations of the autonomic nervous system activity and/or stimulation of the hypothalamic-pituitary-adrenal (HPA) axis (4, 29). However, little is known about the role of the colitis itself on the responsivity of these stress circuits.
Activation of the HPA axis is known to occur after both acute and chronic inflammatory stress, depending on the type and duration of the stressors. For example, acute lipopolysaccharide (LPS) injection results in a transient increase in corticotropin-releasing hormone (CRH) mRNA in the parvocellular paraventricular nucleus (pPVN), an increase in plasma ACTH released from the anterior pituitary, and an increase in plasma corticosterone (Cort) released from the adrenals (23, 25, 36). LPS injection repeated for 6 days resulted in increased CRH mRNA in the pPVN, but it reduced the HPA-axis responses to additional LPS injection (43). However, adjuvant-induced arthritis as a chronic inflammatory stress resulted in decreased CRH mRNA in the pPVN concomitant with the first signs of arthritis (15).
The purpose of the present study is to determine the effect of experimental colitis induced by intracolonic administration of 2,4,6-trinitrobenzenesulfonic acid (TNBS) on the HPA axis, especially on CRH mRNA expression in the pPVN. Colitis induced by TNBS administration is an accepted model of IBD and may also be an inflammatory stress to animals (34). In the present study, we examined the time course of the changes in CRH mRNA in the pPVN, plasma ACTH, and Cort during 14 days after induction of colitis. In addition, we investigated the effects of TNBS colitis on CRH mRNA expression in the pPVN on day 7 after induction of colitis in adrenalectomized animals with Cort pellet replacement (ADX + Cort). The latter study was carried out so that we could determine the effect of negative feedback by endogenous Cort on CRH mRNA expression at this time point of chronic colitis. Finally, we investigated the effect of pair feeding to match the food intake of colitic animals on the changes in CRH mRNA in the pPVN, plasma ACTH, and Cort. Several studies showed that acute inflammation of the colon is accompanied by a marked suppression of food intake (30, 31, 34). In addition, a previous study showed that fasting induces changes in the HPA axis (41). Therefore, we investigated the effect of pair feeding on the HPA axis to determine the contribution of a restriction of food intake on HPA axis during the induction of colitis.
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MATERIALS AND METHODS |
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TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
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Animals
Male Sprague-Dawley rats (SLC, Shizuoka, Japan) weighing 250-300 g were housed three to a cage with free access to standard laboratory chow (CRF-1, Oriental Yeast, Tokyo, Japan) and tap water. They were maintained in a temperature-controlled room (22-24°C) with a 12:12-h light-dark cycle (lights on at 0800). Animals were involved in one of three studies and were moved into the experimental room on the day of the study. All experiments in these studies were conducted according to the National Institutes of Health Guidelines for the Care and Use of Laboratory Animals. The committee of Animal Research in Kyoto Prefectural University of Medicine also approved the experiments.Induction of Colitis
Colitis was induced by intracolonic administration of 0.2 ml of 50% ethanol (vol/vol) containing 20 mg of TNBS (Tokyo Kasei Chemicals, Tokyo, Japan) as previously described (34). Rats were lightly anesthetized with isoflurane, and a polyethylene-60 catheter was inserted rectally into the colon so that TNBS was introduced per the catheter tip that was 8 cm proximal to the anus, approximately at the level of the splenic flexure. Body weight and 24-h food and water intake were measured daily.In the first experiment, rats (n = 35) were killed by decapitation before and on days 1, 3, 7, and 14 after the TNBS enema. After decapitation, brains were removed immediately for in situ hybridization. Trunk blood was collected, and plasma was separated by centrifugation for hormone assays and osmolality determinations. Colons were removed via a midline laparotomy for assessment of the induction of colitis.
Adrenalectomy
In the second experiment, two experimental groups, the ADX + Cort control group (n = 4) and the ADX + Cort TNBS group (n = 4), were used. In both groups, adrenal glands were removed bilaterally by means of two dorsal incisions caudal to the costal margin, and a 100-mg Cort/cholesterol pellet (40%) was implanted subcutaneously while the rats were under pentobarbital sodium (50 mg/kg) anesthesia as previously described (1) (ADX + Cort). All rats were given 0.9% saline in addition to tap water. After 3 days following surgery, rats were infused with TNBS rectally in the ADX + Cort TNBS group and with saline in the ADX + Cort control group. All rats were killed by rapid decapitaion on day 7 after intracolonic infusion of TNBS or saline, and tissues and plasma were collected for assays in a manner similar to those in the first experiment.Pair Feeding
In the third experiment, three groups were used: 1) a control group (n = 4) comprising healthy rats allowed free access to food and water, 2) a colitic group (n = 4) comprising rats infused with TNBS and allowed free access to food and water, and 3) a pair-fed group (n = 4) comprising healthy rats whose daily food intake was matched to that of their pair in the colitic group. The pair-fed group experiment was started 1 day after the colitic group to match the food intake (6). On day 7 after each treatment, rats were killed by decapitation, followed by collection of tissues and plasma in a manner similar to those in the first experiment.Plasma Assays
For all experiments, rats were decapitated between 1200 and 1300. Trunk blood was centrifuged at 3,000 rpm for 10 min, and plasma was stored at
30°C until assay. Plasma ACTH levels
(n = 7) were measured using commercially available kits
(Allegro HS-ACTH kit). Cort (n = 7) was separated from
plasma on a Sephadex LH-20 microcolumn before measurement by
radioimmunoassay (BML, Tokyo, Japan). Plasma osmolarity
(n = 7) was measured by a freezing-point depression
osmolarity (OSMOSTAT, BML).
In Situ Hybridization
After decapitation, brains were quickly removed from the skull and immersed in a fixative containing 4% paraformaldehyde (PFA) in 0.1 M phosphate buffer (PB) for 10 h at 4°C. After cryoprotection in 20% sucrose for 48 h, serial frontal sections (50-µm thickness) of the hypothalamus including the pPVN were cut on a cryostat and collected in 4× standard saline citrate (SSC). The hybridization protocol was similar to those described previously (2, 44). The sections were treated with 0.1 mg/ml proteinase K (Sigma), 10 mM Tris buffer (pH 7.4), and 10 mM EDTA for 10 min at 37°C, 4% PFA in 0.1 M PB for 5 min, and 0.25% acetic anhydride in 0.1 M triethanolamine for 10 min. Sections were subsequently incubated in hybridization buffer containing [35S]cytidine 5'-triphosphate (CTP)-labeled CRH riboprobe for 12 h at 60°C. After the hybridization, sections were washed in 2× SSC containing 50% formamide, RNAase solution, and 0.4× SSC. Sections were mounted onto gelatin-coated microscope slides and exposed to X-ray film (Fuji Imaging plate, Fuji Photo, Japan) for 24 h, after which the slides were apposed to
-max film (Amersham Pharmacia Biotech) for 5 days at
4°C. The specificity of the probes used for this protocol was
previously determined (2).
Quantitative Analysis of mRNA Signals
To quantify the CRH mRNA signals, the radioactivity of each pPVN was measured as photo-stimulated luminescence emitted from the imaging plate and was analyzed using a microcomputer interfaced to an image-analyzing system (BAS2000, Fuji Film) as described previously (44). The results are presented as the mean percentage change from controls.Measurements of Colitis
The severity of colitis was assessed by macroscopic damage scoring and quantification of granulocyte infiltration through measurement of tissue-associated myeloperoxidase (MPO) activity.The macroscopic damage scoring was performed using the scoring system as previously described (28). For macroscopic damage scoring, the colon was visually examined for adhesions and gross morphological changes immediately after death. Then the entire colon was removed and opened by a longitudinal incision to assess inflammation, wall thickness, and the nature of the feces. The scoring of colonic damage was always performed by an observer who was unaware of the treatments.
Immediately after being scored, MPO activity was measured in the distal portion of the colon (2-8 cm proximal to the anus) according to a previously described method (20). The MPO assays were performed in a blinded fashion in coded tubes. The protein concentration was measured by the modified method of Lowry et al. (24) using the Bio-Rad DC test, and MPO activity was expressed in units per gram of tissue protein, with 1 U hydrolyzing 1 µM H2O2/min.
Statistical Analysis
All quantitative findings were presented as means ± SE. In the ADX + Cort study and pair-fed one, CRH mRNA, plasma ACTH and Cort, and MPO activity were compared using the unpaired Student's t-test. In the time course study, statistical significance was determined using one-way ANOVA coupled with Bonferroni protection for multiple comparisons. A P value of <0.05 was considered significant.| |
RESULTS |
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TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
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Time Course Study
Induction of colon damage.
Administration of 20 mg of TNBS induced severe diarrhea and resulted in
hemorrhagic inflammation associated with ulceration and increased wall
thickness in the distal colon after induction of colitis. Thus the
colonic macroscopic damage score and MPO activity for 14 days after
induction of colitis were significantly (P < 0.01)
higher than those of controls (Fig. 1).
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Food consumption and body weight.
TNBS-treated rats ate significantly less (P < 0.001)
during the first 4 days after induction of colitis than they did before induction of colitis, but by day 5, the average food intake
of TNBS-treated rats had returned to pretreatment or control levels (Fig. 2A). TNBS-treated rats
drank significantly (P < 0.05) more water on
days 2, 3, and 4 after
induction of colitis than they did before induction of colitis, but the
average water intake of TNBS-treated rats had returned to pretreatment
or control levels on and after day 5 after induction of
colitis (Fig. 2B). On day 7 after induction of
colitis, plasma osmolarity of TNBS-treated rats did not differ
significantly from control levels (control: 291.0 ± 2.3 osM;
TNBS: 292.6 ± 0.8 osM). Body weight changes were consistent with the decreased levels of food intake, and by day 7, the average body weight of TNBS-treated rats returned to
pretreatment levels but is significantly below that of control by
7.35% (Fig. 2C).
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CRH mRNA in the hypothalamus.
CRH mRNA levels in the pPVN on days 3 and 7 after
induction of TNBS colitis were significantly (P < 0.05 and P < 0.01, respectively) lower than those before
induction of colitis (Fig. 3,
A and B). The average CRH mRNA level in the pPVN
on day 7 after induction of colitis had fallen to 47% of
that before induction of colitis. However, the CRH mRNA level in the
pPVN on days 1 and 14 after induction of colitis
did not differ significantly from the level before induction of
colitis.
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Plasma ACTH and Cort.
The plasma ACTH level on day 1 after induction of colitis
was significantly (P < 0.05) higher than the basal
level, whereas on days 3, 7, and 14 after induction of colitis, the plasma ACTH level had returned to the
basal level (Fig. 4A).
However, the plasma Cort level showed a significant (P < 0.001) increase continuously at all intervals of study, through
day 14 after induction of colitis when compared with the
basal level (Fig. 4B).
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Effect of Adrenalectomy
Induction of colitis in ADX rats without implantation of a Cort pellet resulted in the death of all (n = 10) animals within 3 days after induction of colitis. Our experimental design also included ADX rats that were implanted with a Cort pellet (ADX + Cort) so that they would survive at least 7 days after the induction of colitis.A TNBS treatment in the ADX + Cort group resulted in a significant
increase in MPO activity on day 7 after induction of colitis (P < 0.001) (Fig.
5D), and ADX + Cort
itself caused no increase in MPO activity when compared with intact
controls (Figs. 1 and 5D). The CRH mRNA level in the pPVN in
the ADX + Cort TNBS group was significantly higher than that in
the ADX + Cort control group on day 7 after induction
of colitis (P < 0.001) (Fig. 5A), whereas in the adrenal-intact rats, the CRH mRNA level in the pPVN in the
colitic group was significantly lower than that in the control group
(P < 0.01) (Fig. 3). TNBS treatment in the ADX + Cort groups resulted in no significant change in the plasma ACTH level
on day 7 after induction of colitis (Fig. 5B).
Finally, the plasma Cort level after TNBS administration was within the
range of basal level exhibited by the ADX + Cort groups on
day 7 after induction of colitis (Fig. 5C).
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Effect of Pair Feeding
Body weight changes in the pair-fed group paralleled those in the colitic group (Fig. 2B). Thus no significant differences between these two groups were observed in the 24-h food intake and body weight change after induction of colitis or pair feeding.The CRH mRNA level in the pPVN in the pair-fed group did not differ significantly from the level in the control group (control: 100 ± 14.73%; pair fed: 102.86 ± 14.35%, P = 0.44). Similarly, plasma ACTH and Cort in the pair-fed group did not differ significantly from the level in the control group (ACTH/control: 32.40 ± 5.10 pg/ml; pair fed: 27.92 ± 9.45 pg/ml, P = 0.32; Cort/control: 8.41 ± 2.39 µg/dl; pair fed: 14.20 ± 1.92 µg/dl, P = 0.06).
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DISCUSSION |
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TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
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In the present study, a decrease in CRH mRNA in the pPVN and an increase in plasma Cort were shown on days 3 and 7 after induction of TNBS colitis. It is suggested that the decrease in CRH mRNA observed in TNBS colitis was due to inhibitory feedback by the raised circulating level of Cort. To clarify the role of an elevation of endogenous steroids in the regulation of the HPA axis during colitis, we produced an experimental animal preparation that included surgical adrenalectomy and implantation of a Cort pellet (ADX + Cort). This model maintained the basal level of plasma Cort on day 10 after ADX + Cort (7 days after induction of colitis), which was consistent with a previous report (1). We subsequently examined the HPA-axis responses on that day. In the latter study, TNBS colitis in ADX + Cort animals resulted in a significant increase in CRH mRNA in the pPVN compared with noncolitic animals. This finding clearly showed that the decrease in CRH mRNA associated with the development of colitis in the adrenal-intact rats was mainly due to the inhibitory feedback by the raised endogenous steroids. Previous studies reported similar HPA-axis responses to chronic inflammation that resulted in a decrease in CRH mRNA in the pPVN, a decrease in plasma ACTH, and an increase in plasma Cort at the time of onset of adjuvant-induced arthritis in rats (15, 16). In that model, however, adjuvant-induced arthritis resulted in a decrease in CRH mRNA levels in adrenalectomized animals, indicating that the inhibition of CRH mRNA associated with arthritis is not simply due to changes in the glucocorticoid feedback. The reason for the difference in the apparent importance of the inhibitory feedback by circulating glucocorticoid between the present colitic model and the arthritic one is unclear. However, the difference in the location and the time course of inflammation between these two models should be considered.
It was suggested that systemic administration of LPS can increase CRH
mRNA levels in the pPVN, which are thought to be mediated by a number
of cytokines such as interleukin-1 (IL-1), tumor necrosis factor-
(TNF-), and IL-6 released from activated macrophages (18). In rats, experimental colitis increases plasma
cytokines such as IL-1, TNF-, and IL-6 (6, 19, 35),
suggesting that plasma cytokines are also increased and they might have
some positive effect on the expression of CRH mRNA in the present
model. However, a recent study showed that acute experimental colitis
increased Fos expression in the neurons of the nucleus of the solitary
tract (NTS) in the brain stem and the dorsal horn in the lumbosacral spinal cord, which may reflect the afferent input from the colon (32). Another study suggested that CRH mRNA expression in
the pPVN was under positive feedback control via accending projections from noradrenergic nuclei such as the locus ceruleus (LC) and NTS
(14, 39). Therefore, the colitis in the present study may
also influence CRH mRNA expression via an ascending pathway including
the visceral afferent neurons from the colon. In fact, the findings
from the present study showed that the CRH mRNA level on day
7 after induction of colitis was significantly higher than controls in ADX + Cort groups, in which there was no difference in
the inhibitory feedback by circulating glucocorticoid. These findings
suggested that colitis-induced stimulation to CRH mRNA expression via
cytokines and/or the activating visceral afferent pathway might be
continued at this time in association with the colitis.
It is well known that the synthesis and secretion of ACTH are under inhibitory feedback by glucocorticoid, which acts directly at the anterior pituitary gland (17). In the present study, the plasma ACTH level remained at a basal level after a transient increase on day 1 after induction of colitis. This finding showed that the synthesis and/or secretion of ACTH might be inhibited by glucocorticoid feedback and/or decreased CRH synthesis during the chronic phase of colitis. In the present study, plasma Cort was elevated when measured on days 1, 3, and 7 through 14 days after induction of colitis, despite the low activity of CRH mRNA in the hypothalamus (days 3 and 7) and the pituitary (ACTH, days 3, 7, and 14 after induction of colitis). The reason for this finding is unclear, although the cytokines could be candidates as mediators of this effect based on the findings of a previous study that showed IL-1 enhances Cort secretion by acting directly on the adrenal gland (3, 13).
It has been suggested that the adrenocortical steroids have a protective effect against the lethal insult of acute or chronic inflammation, and this is emphasized by the fact that adrenalectomized animals show increased mortality after acute or chronic inflammation (7, 16). In a recent study using TNBS colitis, adrenalectomy 10 days before induction of colitis increased MPO activity, and exogenous glucocorticoids decreased it as assessed 24 h after induction of colitis (46). In the present study, adrenalectomy 3 days before induction of colitis resulted in a significant increase in mortality after induction of colitis, and exogenous glucocorticoids decreased it. These findings clearly further confirm the importance of adrenocortical steroids in protecting animals from the lethal effects of immunological challenges as they occur in experimental colitis.
A previous study showed that the CRH concentration in the hypothalamus and the serum ACTH level were reduced via a negative feedback by the elevated serum Cort in the fasted animals (41). In the present study, animals showed severe anorexia for 3 days after induction of colitis, consistent with previous reports (30, 31). Therefore, we wanted to determine if the HPA-axis responses observed in colitis were due to the colitis itself or due to the reduced food intake associated with the induction of colitis. The present findings showed that there were no significant differences in CRH mRNA in the pPVN, plasma ACTH, and Cort between normal animals and rats that were pair fed to match the food intake during the 7 days after the treatment used to produce colitis. The results of this food restriction study indicated that the HPA-axis responses observed during induction of colitis were not attributable to the anorexia associated with the introduction of intracolonic TNBS. Moreover, dehydration is known to inhibit the CRH expression in the pPVN (2, 47). Thus we examined whether dehydration occurred during colitis because TNBS colitis induced severe diarrhea. In the present study, water intake and plasma osmolarity in the colitic group were similar to those in the control group on day 7 after induction of colitis. These results indicated that dehydration was also not associated with the decrease in CRH mRNA expression at this time of colitis.
Recent studies showed that CRH in the brain may make a number of contributions to intestinal motor function and inflammation. For example, the activation of CRH receptors in the brain plays a key role in mediating stress-induced gastrointestinal motor alterations through modulation of autonomic outflow (26, 42). Other studies suggested that central CRH played a protective role in stress-induced worsening of colitis (33). In the present study, we demonstrated that rats developed an HPA-axis imbalance including a decrease in CRH mRNA during experimental colitis, which might be associated with intestinal dysfunction and prolonged intestinal inflammation. In addition, a recent clinical study showed that the serum cortisol levels were increased in Crohn's disease patients in association with higher humoral inflammatory activity (40). This indicates that an HPA-axis imbalance may also occur in IBD patients.
In conclusion, we observed a decrease in CRH mRNA in the pPVN during
experimental colitis in rats, which was mainly due to inhibitory
feedback by the raised circulating glucocorticoid. In addition, the
decrease in food intake during colitis was not simply responsible for
these HPA-axis responses. These HPA-axis changes could be involved in
the neuroendocrine-immune network during colitis (Fig.
6). To what extent this HPA-axis
imbalance, especially the decrease in CRH mRNA in the pPVN, influences
colonic dysfunction and/or inflammation needs further clarification.
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Perspectives
CRH is a mediator of the HPA axis, autonomic nervous system, and immune responses in stress (10, 11, 45). It also exerts numerous effects on physiological functions, including appetite control, anxiety-like behaviors, arousal, learning, and memory (10, 11, 38). The basis for these effects is constituted by its distribution in hypothalamic and extra-hypothalamic brain areas, the latter being represented by limbic structures such as the central nucleus of the amygdala (CeA) or by brain stem nuclei such as the LC or NTS (22, 37). In terms of these variations in CRH function, dramatic changes in CRH distribution are expected in both hypothalamic and extra-hypothalamic areas during colitic condition. Clinically, colitic patients present with numerous physiological and psychological symptoms. For instance, some clinicians have expressed the view that IBD may, in part, be a psychosomatic condition, such as depression and anxiety (21). CRH in the pPVN and CeA may be a key mediator of such symptoms, as these regions play important roles in the behaviors mentioned (5, 9). Other clinical studies reported irritable bowel syndrome was seen in patients after an enteric infection or in patients in remission from ulcerative colitis (8). Autonomic disorders associated with CRH may be involved in these phenomena. Recent studies clarified many functions of CRH; not only by distribution, but also by receptor and antagonist studies. With the use of these methods, further experimental investigation of CRH in the brain during colitis will undoubtedly aid our understanding of brain-gut interactions in colonic diseases.| |
ACKNOWLEDGEMENTS |
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This study was supported in part by a grant from the Ministry of Education, Sports, and Culture in Japan.
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FOOTNOTES |
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Address for reprint requests and other correspondence: M. Tanaka, Dept. of Anatomy & Neurobiology, Kyoto Prefectural Univ. of Medicine, Kawaramachi-Hirokoji Kamigyo-ku, Kyoto 602-0841, Japan.
The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
10.1152/ajpregu.00260.2001
Received 14 May 2001; accepted in final form 31 December 2001.
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TOP
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RESULTS
DISCUSSION
REFERENCES
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