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The Clayton Foundation Laboratories for Peptide Biology, The Salk Institute, La Jolla, California 92037
Address all correspondence and requests for reprints to: Wylie W. Vale, Ph.D., The Clayton Foundation Laboratories for Peptide Biology, The Salk Institute, 10010 North Torrey Pines Road, La Jolla, California 92037. E-mail: vale{at}salk.edu
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Introduction |
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There are two receptors for CRF and Ucn, the CRF receptor type 1 (CRF
R1) and CRF receptor type 2 (CRF R2) (9). CRF has low affinity for CRF
R2 and high affinity for CRF R1 (10), whereas Ucn has high affinity for
both (1). Ucn is proposed to function as a ligand for CRF R2 (9). In
the brain, the distribution of Ucn or urotensin-like immunoreactive
fibers is different from that of some CRF and correlates with the
distribution of CRF R2
, but not CRF R1 (1).
Both CRF and Ucn are posited to influence immune functions. Ucn mRNA and peptide were found in human lymphocytes (11), while CRF mRNA was reported in rat thymus and rat/mouse spleen (7, 12). The functions of CRF and Ucn within the context of immune responses are not completely known. Hypothalamic-produced CRF in response to stressors acts through CRF R1 to stimulate the synthesis and release of ACTH by pituitary corticotropic cells (13, 14). ACTH in turn stimulates production of adrenocorticosteroids (13). In addition to the effect on the hypothalamus-pituitary-adrenal (HPA) axis, CRF modulates immune responses in the periphery both directly and indirectly (15). In in vitro studies, CRF has been shown to stimulate B and T lymphocyte proliferation (16, 17). In addition to well established inhibitory effects on POMC (18, 19) and CRF gene expression (18, 20), glucocorticoids are known to be potent antiinflammatory agents (21) and to modulate production of inflammatory factors such as cytokines (22, 23). Although the role of endogenous Ucn in immune function is not yet clear, endogenous Ucn is able to mimic some of the actions of CRF, such as appetite suppression (24). In addition, both peptides modulate immune and inflammatory responses (9). For example, the administration of Ucn suppresses inflammation (25) and cytokine release more effectively than CRF (26), working independently of endogenous corticosteroids (26). Exogenous Ucn limited the clinical course of autoimmune encephalomyelitis more robustly than did CRF (27). The significance of endogenous Ucn in immune system functions, however, remains an open question.
In the present study, we examined the tissue distribution of Ucn mRNA in rat using ribonuclease (RNase) protection assays. We then studied the regulation of Ucn mRNA levels in thymus and spleen, a tissue of high relative Ucn gene expression, to verify the hypothesis that regulation of Ucn mRNA levels in thymus and spleen would be altered after immune activation.
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Materials and Methods |
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Surgery
Jugular vein cannulation. In all rats, a jugular vein
catheter (PE 50, Becton Dickinson and Co., Sparks, MD) was
inserted into the right atrium under light halothane anesthesia 2 days
before experiments. The catheter was filled with heparinized saline,
passed through a subcutaneous tunnel, and exteriorized at the back of
the neck. After the cannulation, rats were housed in individual
cages.
Subcutaneous cannulation. In animals in which ACTH gel or corticosterone was injected, a subcutaneous catheter (PE 20, Becton Dickinson and Co.) was inserted into the back at the same time as jugular vein cannulation. The catheter was filled with saline, passed through a subcutaneous tunnel, and exteriorized at the back of the neck.
Adrenalectomy (Adx). Halothane-anesthetized rats were adrenalectomized bilaterally via a dorsal approach, and implanted sc with slow-release corticosterone pellet (35 mg, 21 day release; Innovative Research of America, Sarasota, FL; Adx + corticosterone). This regimen was chosen for its ability to retain basal CRF and vasopressin mRNA levels in the paraventricular nucleus of the hypothalamus and POMC mRNA levels in the anterior pituitary after Adx (28). A control group of rats (sham) was anesthetized, received the same dorsal incision, and was implanted with a placebo pellet. After surgery, all rats were provided with water containing 0.9% NaCl. Five days later, sham and Adx + corticosterone rats participated in lipopolysaccharide (LPS) experiments. In LPS-injected Adx + corticosterone rats, Adx was verified by the lack of change in plasma corticosterone. In saline-injected Adx + corticosterone rats, Adx was verified by the lack of circadian elevation in plasma corticosterone 8 h after lights-on.
Reagents
LPS (Escherichia coli serotype O26: B6; code 3755,
lot 37H4095) and corticosterone were purchased from Sigma
(St. Louis, MO). ACTH gel (H.P. Acthar gel) was purchased from
Rhone-Poulenc Rorer Pharmaceuticals Inc. (Collegeville, PA).
Experimental procedure
On the day of the experiment, the rats were housed in opaque
sampling cages, and the jugular vein catheter was connected to a
sampling tube to allow for remote sequential blood sampling. After a
period of 2–3 h, experiments were started at 0800–0900 h. The rats
were killed by decapitation after final blood sampling, and the tissues
were removed and frozen in liquid nitrogen.
Exp 1: Effects of iv injection of LPS (50 µg/kg BW) on plasma ACTH, corticosterone, and Ucn mRNA levels in the thymus and the spleen. After blood sampling for measurement of basal plasma ACTH and corticosterone levels, vehicle (saline, 100 µl) or LPS at a dose of 50 µg/kg BW was injected iv at 0 min. Blood was drawn 30, 60, 120, 240, and 360 min later, and stored for future measurements of plasma ACTH and corticosterone. After blood was sampled at 6 h, some rats were decapitated, and organs were harvested. To examine time-dependent changes in Ucn mRNA levels, other rats were decapitated 2 h and 24 h after vehicle or LPS injection (50 µg/kg BW).
Exp 2: Effects of sc injection of ACTH gel (0.8 U/animal) on plasma corticosterone and Ucn mRNA levels in the thymus and spleen. After blood sampling for measurement of basal plasma corticosterone levels (0 min), vehicle (saline, 100 µl), LPS (50 µg/kg BW, iv), or ACTH gel (0.8 U/rat, sc) was injected. ACTH was also administered at 30 and 60 min. This dose regimen was chosen to ensure a prolonged endogenous corticosterone release (29). Blood was drawn 30, 60, 120, 180, 240, 300, and 360 min after LPS injection or first ACTH injection for plasma corticosterone measurement. After sampling at 6 h, the rats were decapitated for tissue collection.
Exp 3: Effects of Adx with corticosterone replacement and LPS injection (50 µg/kg BW) on plasma ACTH and corticosterone and Ucn mRNA levels in the thymus. After blood sampling for measurement of the basal plasma ACTH and corticosterone levels, vehicle (saline, 100 µl) or LPS (50 µg/kg BW, iv) was injected at 0 min in sham or Adx + corticosterone rats. Blood was drawn at 60 and 240 min for ACTH and corticosterone measurements. After the final blood sampling, the rats were decapitated for tissue collection.
Exp 4: Effects of sc injection of corticosterone or restraint stress on plasma ACTH, corticosterone, and Ucn mRNA levels in the thymus. After blood sampling for measurement of the basal plasma ACTH and corticosterone levels, vehicle (100 µl of saline for iv injection and 200 µl of 11% ethanol-containing saline for sc injection), LPS (50 µg/kg BW, iv), a low dose of corticosterone (37.5 µg/rat, sc), or a high dose of corticosterone (125 µg/rat, sc) was injected. Both low and high doses of corticosterone were administered at 0, 30, 60, 120, and 180 min. Some rats that received both vehicle injections were wrapped in cloth towels and restrained by rubber bands and labeling tape for 1 h. Blood was drawn 30, 60, 180, and 360 min after injection or onset of restraint for plasma ACTH and corticosterone measurements. After sampling at 6 h, the rats were decapitated for tissue collection.
RNase protection
Total RNA was extracted using TRI REAGENT (Molecular Research Center, Inc., Cincinnati, OH).
Rat Ucn and glyceraldehyde-3-phosphate dehydrogenase (GAPDH) mRNA
levels were measured simultaneously by RNase protection, using rat
GAPDH as an internal loading control. A 361-nucleotide Ucn antisense
riboprobe (Fig. 1
) specific to the rat
Ucn mRNA was synthesized using T7 RNA polymerase. A 165-nucleotide
GAPDH antisense riboprobe specific to the rat GAPDH mRNA was
synthesized using T3 RNA polymerase. All riboprobes were synthesized in
the presence of [-32P]UTP (3,000 Ci/mmol) and 20
µM UTP, as described (30). The fragments protected by the
Ucn and GAPDH riboprobes are 307 and 135, respectively (Fig. 1).
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Corticosterone and ACTH measurement
Plasma corticosterone and ACTH were measured in duplicate from
unextracted samples. Plasma corticosterone levels were measured with a
commercial immunoradiometric assay kit produced by ICN Biomedicals, Inc. (Costa Mesa, CA). Plasma ACTH levels were
measured with a commercial immunoradiometric assay kit produced by
Nichols Institute Diagnostics (San Juan Capistrano, CA).
Repeated samples from individual rats were analyzed within the same
assay.
Statistical analysis
All values are expressed as the mean ± SEM.
Statistical analyses of these data were performed using one-way ANOVA,
or two-way ANOVA on repeated measures with time and treatment as the
factors (followed by Fisher’s least protected significant difference
or Duncan’s test). P < 0.05 was accepted as
statistically significant.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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). For a preliminary assessment of
tissue distribution of Ucn in rat, a rat Ucn-specific antisense
riboprobe was synthesized and hybridized with total RNA isolated from a
variety of peripheral tissues. Ucn mRNA was abundantly expressed in
thymus, spleen, gastrointestinal tract, and testis; lower levels of
mRNA were detected in the kidney, heart, and liver.
Effects of LPS on HPA axis activity and on Ucn mRNA in the thymus
and spleen
Rats were injected with saline or LPS (50 µg/kg) iv and plasma
ACTH and corticosterone levels were measured. Plasma ACTH and
corticosterone levels immediately before treatment in both saline and
LPS groups were typical of rats under nonstress conditions. Both plasma
ACTH and corticosterone levels in vehicle-injected rats were elevated
in the evening, consistent with the known diurnal rhythms of these
hormones. As expected, iv administration of LPS elicited time-dependent
increases in plasma ACTH and corticosterone levels, with peak
concentrations measured 1 h (mean ± SEM,
820.42 ± 115.73 pg/ml) and 2 h (mean ±
SEM, 522.61 ± 137.34 ng/ml) after injection,
respectively.
Figure 2A shows time-dependent changes in
Ucn mRNA levels in the thymus after iv injection of LPS, which were
statistically significant by using ANOVA. Peak Ucn mRNA levels were
2-fold those of the control values 6 h after LPS injection
(P < 0.05). Ucn mRNA levels in thymus returned to
basal levels 24 h after treatment. By contrast, in the spleen
(Fig. 2B), Ucn mRNA levels were decreased to less than half those of
the control values 6 h after LPS injection (P <
0.05). The decrease in mean values in Ucn mRNA 24 h after LPS
injection was not significant.
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). Administration of
LPS produced a large elevation in plasma corticosterone concentrations.
Similarly, sc injection of ACTH gel also significantly elevated plasma
corticosterone compared with the saline-injected group.
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). The level of thymic Ucn mRNA after the
injection of ACTH was not significantly different from that in LPS
group. In the spleen (Fig. 3C), there were higher mean values in Ucn
mRNA levels in the ACTH-injected group, but the difference was not
statistically significant.
Effects of endogenous corticosterone on thymic Ucn mRNA
To determine whether the effects of LPS on Ucn mRNA required an
increase in endogenous corticosterone, we repeated the previous
experiment using Adx rats in which plasma corticosterone was clamped at
approximately 50 ng/ml (Adx + corticosterone), or sham-operated intact
rats (sham, as a control). In the saline-injected sham rats, plasma
ACTH and corticosterone levels exhibited the expected diurnal variation
(Fig. 4A). Plasma corticosterone in Adx +
corticosterone rats was unchanged throughout the sample period. There
were significant differences in plasma ACTH levels after LPS injection
between sham and Adx + corticosterone rats, probably due to the lack of
negative feedback from glucocorticoids in the latter group. Plasma ACTH
and corticosterone levels increased 1 h after LPS injection in
sham rats. The Adx + corticosterone rats demonstrated substantial ACTH
responses after LPS injection, but no change in corticosterone
levels.
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). While Ucn mRNA in the thymus increased 2-fold
after LPS injection in sham rats, this effect was abolished in Adx +
corticosterone rats.
Induction of thymic Ucn mRNA by corticosterone or restraint
stress
To determine whether Ucn expression responds directly to changes
in plasma corticosterone in the absence of immune challenge, exogenous
corticosterone was administered to intact rats. Administration of low
(35 µg/rat) and high doses (125 µg/rat) of corticosterone elevated
plasma corticosterone concentrations over those of saline-treated rats
30 and 60 min after injection (Fig. 5A).
Plasma corticosterone concentrations at 30 and 60 min and the area
under the curve (AUC) from 0 to 360 min in high doses of
corticosterone- and LPS-injected rats were not different (Fig. 5B). Low
doses of corticosterone injection resulted in plasma corticosterone
concentrations at 30 and 60 min and AUC (0–360 min) that were
intermediate to those of saline- and high corticosterone dose-injected
rats.
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shows effects of corticosterone injections on Ucn mRNA in the
thymus. Ucn mRNA levels in the thymus doubled 6 h after injection
of the high dose of corticosterone compared with saline-injected rats.
This increase was of the same magnitude as that seen in LPS-injected
rats. Injections of the low dose-corticosterone did not elevate Ucn
mRNA expression.
To determine whether Ucn expression could be stimulated by a nonimmune
stress, some saline pretreatment/saline treatment rats were
physically restrained for 1 h. The restraint stress produced
marked elevations of plasma corticosterone levels that were similar in
magnitude and AUC to those of high doses of corticosterone injection
and LPS injection (Fig. 5B). Ucn mRNA in the thymus was stimulated by
restraint stress 6 h after the initiation of restraint to a level
similar to that seen in LPS- or high doses of corticosterone-injected
rats (Fig. 5C).
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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The role of Ucn in the immune system has not been determined. On the other hand, CRF has previously been demonstrated to modulate the immune or inflammatory responses of various tissues, although the significance of such findings has yet to be put in physiological and pathological context. Exogenous administration of CRF has been shown to reduce inflammation and suppress some immune functions (33, 34). In contrast to these reports, it has been demonstrated that administration of CRF antiserum or receptor antagonist decreased acute and subacute inflammations in vivo in several models of inflammation (15, 35, 36). The recent identification of Ucn, however, suggests that Ucn, instead of CRF, may represent an endogenous mediator of some of these effects, because both Ucn and CRF can act through CRF R1 and R2 (1). Further, some antisera previously used were found to detect not only CRF but also Ucn (11). For instance, although the production of CRF-like immunoreactivity had been demonstrated in human T lymphocytes (37, 38), Bamberger et al. (11) clearly demonstrated that Ucn mRNA, but not CRF, was expressed in the human lymphocytes through the use of CRF- and Ucn-specific probes (11).
Antiinflammatory actions of exogenous Ucn have recently been reported (25). Exogenous Ucn was shown to be a potent antiinflammatory factor after thermal injury of skin (25), and an antinecrotic factor following hypoxia (6). Recently, it was shown that exogenous Ucn directly inhibited LPS-induced tumor necrosis factor (TNF) production both in vivo and in vitro more potently than did CRF, supporting the hypothesis postulating an antiinflammatory role for Ucn (26). The role of endogenous Ucn in immune tissues, however, is still unclear. Endogenous Ucn in the immune tissues might act on lymphocytes, in an autocrine or paracrine manner, as lymphocytes have been shown to possess CRF binding sites (39). Ucn secreted locally in a glucocorticoid-dependent manner after immune challenge could possibly modulate cellular immunity or the differentiation and/or proliferation of T lymphocytes in the thymus.
The increase in Ucn mRNA in the thymus is dependent on glucocorticoid production. The thymus has been found to exhibit high concentrations of glucocorticoid receptor (31). In the thymus, glucocorticoids take a major part in the growth of the epithelial cells, differentiation of thymocytes, and regulation of T cell development (32, 40). The molecular mechanisms underlying the regulation of Ucn are currently under investigation. In both the mouse and human Ucn promoters, there is a consensus cAMP response element (CRE) site, which has been shown to mediate the regulation of Ucn expression by cAMP (41). Four base pairs upstream of the CRE site, there is a consensus half-site for the glucocorticoid response element (GRE) with sequence AGAACA in the antisense orientation. It exists in the same position in both mouse and human Ucn promoters. The glucocorticoid receptor has been shown to activate gene expression through both simple GREs or composite GREs, sites that have both GRE and other transcription factor binding sites (42, 43). It is possible that Ucn regulation by corticosterone is mediated through this potential composite GRE in the thymus.
Although Ucn mRNA in the spleen was decreased after LPS challenge, the
decrease was independent of HPA changes. The mechanism of modulation of
Ucn mRNA in the spleen after LPS was not determined in this study.
During activation of the immune system or exposure to nonimmune
stresses, proinflammatory mediators such as interleukin (IL)-1ß,
IL-6, and TNF, are known to be elevated in the systemic circulation
(15, 44), and it has been shown that CRF is regulated by such cytokines
in vivo and in vitro (15). The Ucn promoter has a
CCAAT/enhancer-binding protein site, sequences associated with
cytokine signaling in CRF promoter (40, 45); therefore, it is most
likely that cytokines, such as IL-1ß, IL-6, and TNF, produced
after LPS challenge, might modulate Ucn mRNA. Such cytokine effects
would be expected to modify the humoral immunity and the cellular
immunity in the spleen and thymus, respectively (32).
In summary, our present data demonstrate 1) that the immune-related tissues relatively express high levels of Ucn mRNA, 2) that endotoxin stimulates Ucn mRNA in thymus, whereas it inhibits Ucn mRNA in spleen, 3) that endotoxin-induced stimulation of Ucn mRNA in thymus requires elevations in plasma corticosterone above basal levels, and 4) that high levels of plasma corticosterone can stimulate Ucn gene expression in the absence of immune challenge. Together, these results suggest that Ucn gene expression in the thymus is dependent on corticosterone stimulation. The significance of increased Ucn expression after immune challenge is currently under investigation.
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Acknowledgments |
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Footnotes |
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2 Foundation for Research Senior Investigator.
Received May 3, 1999.
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