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Metabolism Unit, Center for Metabolism and Endocrinology, Department of Medicine, and Molecular Nutrition Unit, Center for Nutrition and Toxicology, NOVUM, Karolinska Institute at Huddinge University Hospital, S-141 57 Huddinge, Sweden
Address all correspondence and requests for reprints to: Wei Liao, M.D., Ph.D., Center for Nutrition and Toxicology, NOVUM, Karolinska Institute, S-141 57 Huddinge, Sweden. E-mail: wei.liao{at}cnt.ki.se
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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(IFN) and induced organ injury,
hypoglycemia, and hyperlipidemia. In GH-primed rats, endotoxin induced
a further increase of serum IFN (but not TNF); and five out of six
of those rats died within 15 h after giving endotoxin. However,
little difference between endotoxin-treated rats with and without IGF-I
priming could be seen. Furthermore, IGF-I infusion altered blood
glucose, urea, and circulating IGF-I levels more than GH infusion.
Therefore, IGF-I does not enhance the biological activities of
endotoxin in the rat, suggesting that the enhancement of endotoxin
effects by GH is via an IGF-I-independent pathway. Priming rats by GH
(but not by IGF-I) induced a further increased response of serum IFN
but not TNF to subsequent endotoxin challenge, suggesting that IFN
rather than TNF is likely to be involved in this process. |
Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Because of its immunomodulatory effects, GH may influence the response
to microbial challenges. We recently demonstrated that treatment of
rats with GH increases the sensitivity to endotoxin in term of
endotoxin-induced organ injury and endotoxin-induced disturbances in
the metabolism of carbohydrates and lipoproteins (8). Endotoxins are a
class of lipopolysaccharide molecules derived from the cell wall of
gram-negative bacteria. Endotoxins mediate the gram-negative septic
shock syndrome, which is characterized by fever, hypotension,
disseminated intravascular coagulation, multiple organ failure, and
disturbances in the metabolism of carbohydrates and lipoproteins. It is
believed that the in vivo biological activities of endotoxin
are largely mediated by the induced secretion of inflammatory
cytokines, i.e. tumor necrosis factor (TNF), interleukins 1
and 6, and interferon gamma (IFN).
Thus, it is reasonable to speculate that the observed enhancement of the biological activities of endotoxin induced by GH in the rat may be mediated by IGF-I. However, in the present study we showed that, in a striking contrast to GH, IGF-I infusion does not enhance the biological activities of endotoxin in the rat, suggesting that the enhancement of endotoxin effects by GH is via an IGF-I-independent pathway.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Animals and experimental procedure
Male Sprague-Dawley rats (
7 weeks old) were used. They were
maintained under standardized conditions with free access to chow and
water and allowed to adapt to the environment for at least 1 week
before starting the experiment. The light cycle hours were between
0600 h and 1800 h.
Seventy-one rats were used in three separate experiments. In each experiment, four groups of animals were used, and each group consisted of six animals if not otherwise stated. The study was approved by the institutional Animal Care and Use Committee.
In the first experiment, two groups of animals received GH by constant
infusion from osmotic minipumps (model 2001) implanted sc under ether
anesthesia at the start of the experiment (1500 h on day 0); the other
two groups of animals were sham-operated. GH was infused at a rate of 8
µg/rat·h (0.75 mg/kg·day) for 4 days. The GH dose was chosen, as
this dose restores the induction of hepatic LDL receptors by estrogen
in hypophysectomized rats (9). Our previous studies have also shown
that this dose of GH enhances endotoxin activity in the rat (8). At
approximately 1900 h on day 3, endotoxin (5 mg/kg BW, using 0.15
M NaCl as vehicle) or the same volume of 0.15 M
NaCl was injected ip to GH-primed rats and to sham-operated rats. Food
was withdrawn at the time when endotoxin was injected as endotoxin
induces anorexia. One and a half hours and 4.5 h after endotoxin
injection, blood was taken from the retroorbital plexus by using a
capillary tube under light ether anesthesia. Each sampling was
approximately 1 ml. Sera were separated for the assays. Samples taken
1.5 h after endotoxin injection were assayed for TNF; and samples
taken 4.5 h after endotoxin injection were assayed for IFN,
glucose and urea. The rationale for this was that TNF and IFN peak
around 1.5 h (10, 11, 12) and 4.5 h (13), respectively, after
endotoxin challenge. Twenty-four hours after endotoxin injection, rats
were again given food ad libitum. Animals were observed for
a period of 1 week.
The second experiment was designed exactly the same as described above for the first experiment with the exception that, instead of GH, IGF-I was infused by osmotic minipumps (model 2ML1). IGF-I was infused at a rate of 23 µg/rat·h (2.1 mg/kg·day) for 4 days. The IGF-I dose was chosen, as this dose normalizes plasma IGF-I levels in hypophysectomized rats (14).
In the third experiment, rats were infused with IGF-I and then injected with endotoxin as described above. The experiment was terminated 14 h after endotoxin injection by sampling blood into EDTA-containing tubes (Becton Dickinson Vacutainer Systems Europe, B.P. 37-38241, Meylan Cedex, France) via puncture of the abdominal aorta under light ether anesthesia. Plasma was then separated for the assays of renal and liver function, glucose and lipoproteins, etc.
Assays
Serum TNF was measured using the mouse ELISA kit (FactorTest-X
TNF, Genzyme corporation, Cambridge, MA) according to the instructions
by the manufacturer. The kit has full cross-reactivity with rat TNF
(determined by Genzyme corporation, Cambridge, MA). The samples were
diluted appropriately and assayed in duplicate together with the
provided standards. The absorbances were measured at 450 nm by Bio-Rad
Microplate Reader (model 450), and the data were analyzed by using
Microplate Manager 2.1 software (Bio-Rad Laboratories, Richmond, CA).
The intraassay and interassay coefficients of variation of the kit were
3.4 and 7.1%, respectively. The recovery was 90%. The sensitivity was
15 pg/ml. Linear regression analysis of the standard concentration
ranging between 35 and 2240 pg/ml resulted in a correlation coefficient
larger than 0.995.
Serum IFN were measured using the mouse ELISA kit (InterTest-
IFN, Genzyme Corp., Cambridge, MA) according to the instructions by
the manufacturer. The kit is well cross-reactive with rat IFN (15).
The samples were diluted appropriately and assayed in duplicate
together with the provided standards. The absorbances were measured,
and the data were analyzed as described above. The intraassay and
interassay coefficients of variation of the kit were 4.2 and 6.4%,
respectively. The recovery was 95%. The sensitivity was 5 pg/ml.
Linear regression analysis of the standard concentration ranging
between 20 and 1620 pg/ml resulted in a correlation coefficient larger
than 0.997.
Plasma IGF-I was measured by RIA using a polyclonal rabbit antihuman
IGF-I antiserum. The labeled IGF-I used as tracer is a truncated
variant of IGF-I, des(1, 2, 3)rhIGHF-I. In this variant, three amino acids
are missing from the amino terminal, resulting in a lower affinity for
the binding proteins. After acid ethanol extraction of the samples (16)
and subsequent overnight incubation with the antibodies and tracer at
room temperature, the immune complex was precipitated with a second
antibody (polyclonal antirabbit IgG antibody) in the presence of
polyethylene glycol. After centrifugation, the pellet was counted in a
counter, using recombinant human IGF-I as standard. The
coefficients of variation of the intraassay and interassay were 3.1 and
10%, respectively. The recovery of the assay was 98.5%. The assay has
negligible cross-reactivity against proinsulin, insulin, and IGF-II.
There is high cross-reactivity between human and rat IGF-I.
Plasma urea, creatinine, alanine-amino transferase (ALT),
aspartate-amino transferase (AST), gamma-glutamyl transferase (-GT),
lactate dehydrogenase (LDH), amylase, albumin, bilirubin, lactate,
glucose, total cholesterol, and triglycerides were determined
individually by clinical routine techniques as described earlier
(8).
Analysis of plasma lipoprotein profile was performed by fast protein liquid chromatography (17, 18). Equal volumes of plasma from every rat in each group were pooled (5 ml), and the density was adjusted to 1.21 kg/liter with solid potassium bromide. After ultracentrifugation at 100 x 103 g for 48 h, the supernatant (lipoprotein fraction) was adjusted to 2 ml by addition of the elution solution (0.15 M NaCl, 0.27 mM EDTA, 3 mM sodium azide, pH 7.3). After filtration through a 0.45 µm filter, 1 ml (corresponding to 2.5 ml plasma) was injected onto a 54 x 1.8 cm Superose 6B column; 2 ml fractions were collected at a flow rate of 1 ml/min. Fractions were assayed for total cholesterol and triglycerides.
Statistics
Data are presented as means ± SEM and analyzed
by using Statistica software (StatSoft, Tulsa, OK). One-way ANOVA was
used to evaluate the presence of significant differences between
groups, followed by post-hoc comparisons of the group means according
to the method of Tukey. When appropriate, post-hoc comparisons were
adjusted for unequal sample sizes by Spjøtvoll and Stoline. Student’s
t test was used to evaluate the significances of difference
in serum cytokines where only two groups (i.e.
endotoxin-treated groups primed with and without GH in the first
experiment) were compared.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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, controls and animals
treated only with GH had no detectable serum TNF. Serum TNF increased
markedly after endotoxin injection, reaching levels of approximately
120 ng/ml. Serum TNF in GH-primed rats treated with endotoxin was not
higher than that in the animals treated only with endotoxin. Four and a
half hours after endotoxin injection, blood was taken and serum was
separated for IFN assay and also for glucose and urea assays. As for
TNF, controls and animals treated only with GH had no detectable serum
IFN (Fig. 1A). Endotoxin injection markedly increased serum IFN.
Compared to animals given only endotoxin, serum IFN was doubled in
GH-primed rats treated with endotoxin. Endotoxin injection also reduced
blood glucose and increased blood urea. However, GH-primed rats treated
with endotoxin showed much more severe hypoglycemia and higher blood
urea than the rats given only endotoxin. Animals receiving only GH did
not show any visible abnormality. In endotoxin-treated animals,
diarrhea occurred, and these animals were clearly less active than
normal rats. After endotoxin injection, GH-primed rats became very
sick. The general appearance of these rats was similar to what was
observed in our previous study (8), i.e. they had severe
diarrhea, ruffled furs, and were lethargic. No animals died among the
controls or those treated only with GH; one animal died in the
endotoxin-treated group, whereas five of six animals died in GH-primed
rats treated with endotoxin (Fig. 1A). All deaths occurred between 5
and 15 h after endotoxin injection. Twenty-four to 48 h after
endotoxin injection, the surviving animals recovered.
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, respectively.
Blood glucose and urea were also measured 4.5 h after endotoxin
injection. As shown in Fig. 1B
, controls and animals treated only with
IGF-I had no detectable circulating TNF and IFN. Serum TNF and
IFN increased markedly again after endotoxin injection. Serum TNF
seemed to be slightly lower in IGF-I-primed rats treated with endotoxin
than in those given only endotoxin, whereas there was no difference in
serum IFN between endotoxin-treated rats with and without
IGF-I-priming. Clearly, IGF-I did not show any synergistic effect with
endotoxin on blood glucose. Blood urea was not significantly higher in
IGF-I-primed rats treated with endotoxin than in rats given only
endotoxin. The general appearance of IGF-I-primed rats treated with
endotoxin was not distinguishable from that observed in rats treated
only with endotoxin. Animals receiving only IGF-I did not show any
visible abnormality. Again, in endotoxin-treated animals, diarrhea
occurred and these animals were clearly less active than normal rats.
In this experiment, no animals died among the controls, those treated
only with IGF-I or endotoxin. Only one of six animals died 24 h
after endotoxin injection in the group of IGF-I-primed rats treated
with endotoxin (Fig. 1B).
In the third experiment, blood was taken 14 h after endotoxin
injection to determine if IGF-I-primed rats had an increased organ
injury and more severe disturbances in the metabolism of carbohydrates
and lipoproteins. IGF-I infusion reduced plasma glucose, urea, amylase,
and albumin (Table 1) and slightly increased plasma
total cholesterol and triglycerides (Fig. 2A), mainly
due to an elevation within the very low density lipoprotein fraction
(Fig. 2, B and C). Endotoxin had clear injurious effects, which is
consistent with our previous study (8). Thus, plasma levels of urea,
creatinine, ALT, AST, -GT, bilirubin, and lactate were increased
after endotoxin injection (Table 1). Endotoxin decreased plasma
glucose, amylase and albumin (Table 1). Endotoxin increased plasma
levels of total cholesterol and triglycerides (Fig. 2A). The
endotoxin-induced increase in plasma cholesterol and triglycerides
occurred within the apoB-containing lipoproteins, i.e. very
low, intermediate, and low density lipoproteins (Fig. 2, B and C). The
injurious effects of endotoxin did not appear to be more pronounced in
IGF-I-primed rats. Compared to animals treated only with endotoxin,
there was no deterioration in IGF-I-primed rats treated with endotoxin
as judged by plasma urea, creatinine, amylase, bilirubin, and lactate.
ALT, AST, -GT, and LDH also were not significantly higher in
IGF-I-primed rats treated with endotoxin than in rats treated only with
endotoxin (Table 1). IGF-I did not show any synergistic effect with
endotoxin on blood glucose. IGF-I-primed rats treated with endotoxin
did not develop more pronounced hyperlipidemia than did the animals
treated only with endotoxin (Fig. 2).
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The plasma samples for IGF-I assay after GH infusion were obtained from
the experiment in which we previously showed that GH markedly enhances
the in vivo biological activities of endotoxin (8). After
the infusion of GH, plasma IGF-I increased by approximately 20% (Fig. 3A), together with a 10% reduction in plasma glucose
but no reduction in plasma urea (see Ref.8). On the other hand, IGF-I
infusion almost doubled the circulating IGF-I levels (Fig. 3B),
together with a 36% reduction in both plasma urea and glucose (Table 1). Similar results comparing the effects of GH and IGF-I on blood
glucose and urea are shown in Fig. 1. The infusion of GH reduced blood
glucose by 13% and had no effect on blood urea (Fig. 1A), whereas the
infusion of IGF-I reduced blood glucose by 19% and reduced blood urea
by 30% (Fig. 1B). Therefore, IGF-I infusion used in the present study
resulted in markedly increased plasma levels of apparently biologically
active IGF-I but did not enhance the in vivo biological
activities of endotoxin.
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), as described by others (19). Clearly, GH
treatment did not reverse the endotoxin-induced reduction of plasma
IGF-I (Fig. 3A), probably reflecting the resistance to GH in endotoxin
shock. Whether IGF-I had any effect on the endotoxin-induced reduction
of plasma IGF-I could not be addressed because the assay does not
distinguish endogenous from exogenous IGF-I. |
Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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but not TNF to subsequent endotoxin challenge, suggesting that IFN
rather than TNF is likely to be involved in this process. IGF-I-primed
rats subsequently treated with endotoxin did not show any further
increase in serum TNF and IFN, suggesting that, in vivo,
IGF-I does not prime macrophages and lymphocytes for an increased
synthesis and release of inflammatory cytokines.
It is believed that TNF, interleukins 1 and 6, and IFN play
important roles in the mediation of the in vivo biological
activities of endotoxin. TNF administration to animals mimics endotoxic
shock (21, 22, 23); and passive immunization against TNF prevents the
lethal effect of endotoxin and gram-negative bacteremia in animals (24, 25). TNF also induces the synthesis and secretion of other important
inflammatory cytokines, such as interleukins 1 and 6 (26), thus
establishing the central role of TNF in the mediation of the biological
activities of endotoxin. However, we found that GH infusion to rats
increased endotoxin-induced lethality without an increased TNF response
to endotoxin, suggesting that the enhancement of the in vivo
biological activities of endotoxin by GH is not likely to be due to GH
priming of macrophages for an increased synthesis and secretion of TNF.
It has been shown that in vitro treatment of human monocytes
with GH had either no effect or inhibited the endotoxin-induced
production of TNF and interleukin 1 (27, 28). In vivo, GH
pretreatment blunts the plasma increase in TNF and interleukins 1 and 6
in response to subsequent challenge by endotoxin in the calf (29) or by
Escherichia coli bacteria in the mouse (30). Taken together,
these studies support the notion that GH treatment does not enhance the
responses of TNF (and interleukins 1 and 6) to subsequent challenge
with inflammatory stimuli. However, another study showed that in
vivo treatment of hypophysectomized rats with GH induces an
enhanced synthesis of TNF by macrophages in response to subsequent
endotoxin challenge in vitro (31). This may suggest that
GH-treated hypophysectomized rats are different from GH-treated normal
rats in response to endotoxin challenge, or alternatively, the
macrophages isolated from GH-treated rats respond to endotoxin
challenge differently from the in vivo setting.
The lymphocyte-derived cytokine, IFN, also plays important role in
the mediation of endotoxin effects in vivo. Anti-IFN
antibodies can prevent the endotoxin-induced Shwartzman reaction (32)
and reduce the lethality from endotoxic shock (33) and gram-negative
bacteria (34). IFN is synergistic with TNF in inducing lethality in
animals (35). Hence, endogenous IFN plays an important role in the
pathogenesis of events leading to endotoxic shock. In the present
study, we showed that GH-primed rats treated with endotoxin had a
further increase in serum IFN and an increased lethality, suggesting
an important role of IFN as a mediator of the GH-induced
potentiation of endotoxin effects.
In contrast to our study, GH adminstration to hypophysectomized rats actually enhances the resistance to experimental Salmonella typhimurium infection (36), presumably by priming macrophages for an increased production of reactive oxygen intermediates (37) and TNF (31). GH administration to mice also reduces the death from subsequent challenge with Escherichia coli bacteria without increasing plasma cytokines (TNF, and interleukins 1 and 6) (30). The differences in choosing the animal models, the inflammatory stimuli, the GH administration modes (infusion or bolus injections), and the doses and periods of GH exposure may be in part accounted for the differences among these studies. Thus, GH therapy in critical patients with infection and endotoxemia could have either beneficial or detrimental consequences. Although it may presently only be speculated on, our results strengthen the notion that caution should be exerted when considering GH treatment in patients with catabolic conditions complicated with endotoxemia and infections (8), and may imply that IGF-I treatment could be preferable in such situations.
There exist marked species differences in the sensitivity to endotoxin.
Rats and mice are rather resistant to endotoxin, as compared with
primates (including humans), sheep, pigs, and rabbits (38). Endotoxin
administration to rats results in a dramatic (by 80–90% after 1–4 h)
but transient (normalized after 24 h) reduction of plasma GH
levels (19), whereas it increases plasma GH levels in humans (39) and
sheep (40). TNF inhibits basal and GH-releasing hormone-stimulated GH
secretion in vitro from cultured rat anterior pituitary
cells (41). TNF reduces plasma levels GH and IGF-I in the rat (42).
However, anti-TNF antibody attenuates endotoxin-induced reduction of
IGF-I but not GH (42). IFN also inhibits GH secretion in
vitro from cultured rat anterior pituitary cells (43). Thus, TNF
and IFN may play important roles in mediation of endotoxin-induced
reduction of plasma GH. The reduction of plasma GH may attenuate the
endotoxic effects and thus provide an important protective mechanism
against endotoxin in the rat.
In summary, GH enhances endotoxin effects in the rat, thereby
increasing the endotoxin-induced lethality. IGF-I is not likely to be
the mediator because IGF-I does not enhance the biological activities
of endotoxin. GH-primed rats had markedly increased response in serum
IFN but not TNF to endotoxin challenge, suggesting that priming
lymphocytes induced by GH for an enhanced synthesis and secretion of
IFN to subsequent endotoxin challenge is likely to be involved in
this potentiating effect. Further studies are needed to fully establish
the critical importance of IFN in this situation.
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Acknowledgments |
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Footnotes |
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Received May 29, 1996.
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References |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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, and acute
lethality in mice by toxic and non-toxic forms of lipid A. J
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, cortisol, and thromboxane-B2 responses to endotoxin
in vivo. Endocrinology 134:1082–1088 by rat macrophages:
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Endocrinology 128:989–996, a mediator of lethal
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Exp Med 171:1853–1869 in the
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in
experimental gram-negative sepsis. J Infect Dis 166:331–335[Medline]
as a mediator of the
lethality of endotoxin and tumor necrosis factor-. J Immunol 149:1666–1670[Abstract]
inhibits growth hormone secretion from anterior pituitary cells.
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| Molecular Endocrinology | Recent Prog. Horm. Res. | All Endocrine Journals |
,
P < 0.002 vs. control; 
,
P < 0.001 vs. control; *,
P < 0.01 vs. LPS; §,
P < 0.005 vs. LPS.
