Departments of 1 Surgery and 2 Medicine, University of Colorado Health Sciences Center, Denver, Colorado 80262; and 3 Department of Surgery, Northwestern University, Chicago, Illinois 60611
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ABSTRACT |
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Interleukin (IL)-11, like other members of the
gp130 receptor class, possesses anti-inflammatory properties. We
hypothesized that IL-11 pretreatment would attenuate endotoxin
[lipopolysaccharide (LPS)]-induced lung inflammation
and diminish injury to endothelium-dependent and -independent
mechanisms of pulmonary vasorelaxation that require cGMP in
Sprague-Dawley rats. LPS (20 mg/kg ip) increased lung tumor necrosis
factor (TNF)- compared with the saline control (0.7 ± 0.15 ng/g lung wet wt for control vs. 3.5 ± 0.09 ng/g lung wet wt for LPS; P < 0.05). IL-11
(200 mg/kg ip) injected 10 min before LPS administration attenuated the
LPS-induced lung TNF-
levels (1.6 ± 0.91 ng/g lung wet wt;
P < 0.05 vs. LPS). IL-11 also
diminished LPS-induced lung neutrophil sequestration as assessed by
myeloperoxidase units (2.1 ± 0.25 U/g lung wet wt for saline and
15.6 ± 2.02 U/g lung wet wt for LPS vs. 7.07 ± 1.65 U/g lung wet wt for LPS plus IL-11; P < 0.05). Similarly, TNF-
binding protein (175 mg/kg) attenuated
LPS-induced myeloperoxidase activity (6.04 ± 0.14 U/g lung wet wt;
P < 0.05). Both IL-11 and TNF-
binding protein similarly attenuated LPS-induced endothelium-dependent vasomotor dysfunction with improved relaxation responses to
10
7 and
10
6 M acetylcholine and
A-23187 in phenylephrine-preconstricted isolated pulmonary artery rings
(P < 0.05 vs. LPS).
Endothelium-independent relaxation responses to sodium nitroprusside
were also improved after LPS at 10
6 M
(P < 0.05 vs. LPS). Moreover, IL-11
decreased endotoxin-induced mortality in CF1 mice from 90 to 50%
(P
0.05 vs. LPS). Therefore, IL-11
prevents LPS-induced lung TNF-
production, neutrophil sequestration, and pulmonary vasomotor dysfunction. We conclude that IL-11 possesses anti-inflammatory activity that protects against LPS-induced lung injury and lethality.
tumor necrosis factor-; neutrophil; lung myeloperoxidase; guanosine 3',5'-cyclic monophosphate; gp130
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INTRODUCTION |
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ENDOTOXIN [lipopolysaccharide
(LPS)]-induced lung injury is associated with increased
production of tumor necrosis factor (TNF)- (6, 7, 28, 47) and
sequestered pulmonary neutrophils (36). This LPS-induced lung
inflammation results in pulmonary vascular endothelial and smooth
muscle injury (24, 36, 38). Injury of pulmonary vascular endothelium
and smooth muscle after LPS impairs endothelium-dependent and
-independent mechanisms of vasorelaxation that require the production
of cGMP (14). This experimental injury in rats appears to be mediated,
in part, by lung sequestration of neutrophils because neutrophil
depletion prevents LPS-induced histological injury and vasomotor
dysfunction (36). Interleukin (IL)-11, a multifunctional cytokine that
stimulates the gp130 transmembrane-receptor subunit (32), is
biologically related to IL-6, leukemia inhibitory factor, oncostatin-M,
ciliary neurotrophic factor, and cardiotrophin-1 (2, 9, 13, 31, 49).
IL-11 is currently administered to thrombocytopenic patients as a
hematopoietic stimulant (16); however, it also reduces murine
circulating TNF-
(42) and alveolar macrophage TNF-
production
after LPS treatment (34). Consistent with these anti-inflammatory observations, IL-11 treatment also attenuates swine mortality in
staphylococcal enterotoxin-induced toxic shock (1).
We hypothesized that IL-11 would attenuate LPS-induced pulmonary
TNF- production, neutrophil accumulation, and impairment of
endothelium-dependent and endothelium-independent cGMP-mediated pulmonary vasorelaxation. To study pulmonary vasomotor function, we
examined the effect of IL-11 on the LPS-induced impairment of the
following vasorelaxation mechanisms:
1) endothelium-dependent, receptor-dependent cGMP-mediated vasorelaxation [response to
acetylcholine (ACh)], 2)
endothelium-dependent, receptor-independent cGMP-mediated vasorelaxation (response to A-23187), and
3) endothelium-independent relaxation by direct stimulation of smooth muscle soluble guanylate cyclase with sodium nitroprusside (SNP). To study the role of TNF-
in these LPS-induced parameters of lung injury, we examined the effect
of TNF-
binding protein (TNFBP).
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MATERIALS AND METHODS |
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Reagents. Standard reagents with the exception of A-23187 (Calbiochem, La Jolla, CA) were obtained from Sigma (St. Louis, MO). Fresh solutions were prepared daily with either deionized water or normal saline as the diluent.
Animal housing and acclimatization. Animals received humane care in compliance with the Guide for the Care and Use of Laboratory Animals published by the National Institutes of Health [DHEW Publication No. (NIH) 85-23, Revised 1985, Office of Science and Health Reports, DRR/NIH, Bethesda, MD 20892]. Male Sprague-Dawley rats (Sasco, Omaha, NE) weighing 300-350 g were quarantined in quiet, humidified, light-cycled rooms for 2-3 wk before use. The rats were allowed ad libitum access to food and water throughout quarantine and up to the time of the experiment. Experiments were conducted between 7 AM and 2 PM.
Experimental protocol. Awake, fed rats
were administered LPS (Salmonella
typhimurium, 20 mg/kg ip; Sigma) that was freshly prepared in 1 ml of 0.9% saline. Control rats received an equal volume
of saline, and the treated groups received recombinant human IL-11 (200 mg/kg ip; Genetics Institute, Cambridge, MA). To study the influence of
TNF- after LPS treatment, TNFBP (175 mg/kg ip; Amgen, Boulder, CO)
was delivered. It is recombinant human TNFBP as expressed in
Escherichia coli as the construction of two 4-domain-soluble p55 (extracellular) receptor chains of TNF-
linked by a polyethylene glycol bridge (37). Both IL-11 and TNFBP were
given 10 min before the administration of saline or LPS. To harvest
tissue, the rats were anesthetized with pentobarbital sodium (50 mg/kg
ip). A median sternotomy was performed, and heparinization was achieved
by injection of heparin sodium (500 USP) through the right ventricle.
The lung tissue was homogenized to assess TNF-
at 2 h and lung
neutrophil accumulation at 6 h, and main branch pulmonary arteries were
isolated and buffer perfused to examine vasorelaxation mechanisms 6 h
after treatment. All treated rats survived the 6-h experimental period.
Lung TNF- assay. After removal of
main branch pulmonary arteries, both lungs were externally rinsed with
normal saline, blotted dry, and frozen at
70°C. The left
lung was used for the quantification of TNF-
(in ng/g lung wet wt)
by a mouse enzyme-linked immunosorbent assay (ELISA). The left lung was
homogenized for 30 s (Virtishear homogenizer, Virtis, Gardner, NY) in 4 ml of 20 mM potassium phosphate buffer, pH 7.4, and ultracentrifuged
for 30 min at 40,000 g at 4°C. The
supernatants were removed, divided into aliquots, and assayed for
TNF-
by ELISA according to the manufacturer's directions (Genzyme
Diagnostics, Cambridge, MA).
Lung myeloperoxidase assay. The right
lung was homogenized and centrifuged as described in
Lung TNF- assay. The
remaining pellet was resuspended in 4 ml of 50 mM potassium phosphate
buffer, pH 6.0, containing 0.5 g/dl of centrimonium bromide. The
resuspended pellets were sonicated for 90 s at full power (ultrasonic
cell disrupter, Kontes, Vineland, NJ), incubated in a 60°C water
bath for 2 h, and centrifuged for 10 min in an Eppendorf centrifuge (Beckman Microfuge 12, Beckman Instruments, Irvine, CA). Supernatant (0.1 ml) was added to 2.9 ml of 50 mM potassium phosphate buffer, pH
6.0, containing 0.167 mg/ml of
o-dianisidine and 5 × 10
4 M hydrogen
peroxide; absorbance at 460 nm was measured from 1 to 3 min (Beckman
DU7, Beckman Instruments). Units of myeloperoxidase (MPO) per gram of
lung wet weight were calculated with the equation
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Isolated pulmonary artery ring preparation. The method for harvesting isolated pulmonary artery rings has been previously described (36). After 6 h, the heart and lungs were removed, and the right and left pulmonary arteries were dissected free and placed in Earle's balanced salt solution (EBSS) at 4°C. Under magnification, the surrounding tissue was dissected from the pulmonary arteries. The arteries were cut into rings 3-4 mm in length; two pulmonary artery rings (right and left) were obtained from each animal. Care was taken during this process to avoid endothelial injury. EBSS is a standard physiological salt solution and contains 1.80 mM CaCl2, 0.83 mM MgSO4, 5.36 mM KCl, 116.34 mM NaCl, 0.40 mM Na2HPO4 (dibasic), 5.50 mM D-glucose, and 19.04 mM NaHCO3.
The pulmonary artery rings were placed on 11-mil stainless steel wires and suspended in individual 10-ml organ chambers containing EBSS at 37°C. The organ chambers were surrounded by water jackets and continually warmed. Ring tension was determined by use of a force-displacement transducer (Grass FT03, Grass Instruments, Quincy, MA) attached to each steel wire apparatus. Force displacement was recorded at 0.67 Hz with a MacLab Data Interface Module (ADI Instruments, Milford, MA) on a Macintosh Quadra 650 computer (Apple, Cupertino, CA). Each organ chamber was supplied with a continuous flow of bubbling gas (21% oxygen, 5% carbon dioxide, and 74% nitrogen) at 40 ml/min. This gas flow produced a PO2 of 100-110 mmHg and a pH of 7.4.
Pulmonary vasorelaxation by cGMP-mediated
mechanisms. Cumulative concentration-response curves
were generated for ACh, A-23187, and SNP. The optimal resting
mechanical tension (passive load) for pulmonary artery rings of this
size was determined in a prior study (14) to be 750 mg. The rings were
suspended at 750 mg and allowed to reach a steady state for 1 h, during
which time the EBSS was changed every 15 min. A given ring was
preconstricted with phenylephrine (PE) to achieve a PE-induced ring
tension between 200 and 400 mg. Although LPS impairs mechanisms of
pulmonary vasorelaxation, it does not influence the pulmonary artery
1-adrenergic-dependent mechanisms of pulmonary vasoconstriction (14). Cumulative
concentration-response curves were then generated from
10
9 to
10
6 M for ACh, A-23187, and
SNP. During the generation of these curves, the ring was allowed to
reach a steady state, usually requiring 2-3 min, before being
advanced to the next higher concentration. The ring tension remaining
in the rings in response to each dose of vasorelaxing agent is
expressed in milligrams of PE-induced tension.
Survival response. To examine the influence of IL-11 on LPS-induced mortality, male CF1 mice (n = 10/group; Sasco) were injected intraperitoneally with E. coli LPS (100 mg/kg, serotype 055:B5; Sigma) or IL-11 (200 mg/kg) plus LPS and assessed every 6 h through 60 h.
Statistical analysis. Statistical
analyses were performed with a Macintosh Quadra 650 computer and
StatView software (Brain Power, Calabasas, CA). Data for TNF- and
lung neutrophil accumulation and vasorelaxation responses are presented
as means ± SE. Statistical evaluation utilized standard one-way
analysis of variance with post hoc Bonferroni-Dunn test. Survival
results were analyzed by
2 test.
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RESULTS |
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Lung TNF- levels. Two hours after
LPS treatment, lung TNF-
levels were reduced by 56% with IL-11
pretreatment. After a saline injection into control rats (Fig.
1), 0.67 ± 0.15 ng/g lung
wet wt of TNF-
was present; in rats given LPS, the level of TNF-
increased to 3.5 ± 0.09 ng/g lung wet wt at 2 h
(P < 0.05 vs. control level). If
IL-11 was administered 10 min before LPS, measurable lung TNF-
decreased to 1.6 ± 0.91 ng/g lung wet wt
(P < 0.05 vs. LPS and control
values). IL-11 alone did not change lung TNF-
values relative to the
control value (0.35 ± 0.12 ng/g lung wet wt;
P < 0.05 vs. LPS and IL-11 plus LPS
values).
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Lung neutrophil accumulation (MPO).
Endotoxin also increased lung neutrophil accumulation as indirectly
assessed with a marker of neutrophil presence, MPO. Similar to the
TNF- response, IL-11 pretreatment diminished LPS-induced lung
neutrophil accumulation (55%) as did TNFBP treatment (61%) (Fig.
2). After saline injection, lung MPO was
2.1 ± 0.25 U/g lung wet wt; in rats given LPS, MPO increased to
15.6 ± 1.02 U/g lung wet wt after 6 h
(P < 0.05 vs. control value).
Pretreatment with IL-11 10 min before LPS treatment attenuated lung MPO
to 7.07 ± 1.65 U/g lung wet wt (P < 0.05 vs. control and LPS values). Similar pretreatment with TNFBP
resulted in attenuation of lung MPO, with a measured value of 6.04 ± 0.14 U/g lung wet wt (P < 0.05 vs. control and LPS). IL-11 alone did not influence lung neutrophil
accumulation (MPO 3.6 ± 0.59 U/g lung wet wt).
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Influence of IL-11 on cGMP-mediated pulmonary vasorelaxation. We next examined the effect of IL-11 on endothelium-dependent and -independent mechanisms of pulmonary vascular smooth muscle relaxation that require the generation of cGMP. Concentration-response curves to ACh, A-23187, and SNP were generated in pulmonary arteries from rats treated with IL-11 alone.
Administration of IL-11 did not influence cGMP-mediated vasorelaxation (data not shown) as assessed by evaluation of cumulative dose responses for EC50 or by an absolute vasorelaxation response. Neither endothelium-dependent [both receptor-dependent (ACh) and receptor-independent (A-23187)] nor endothelium-independent (SNP) pathways were different from those in control rats.
Effects of IL-11 or TNFBP on endotoxin-induced
impairment of cGMP-mediated pulmonary vasorelaxation.
Endotoxin administration produced significant impairment of
endothelium-dependent, receptor-dependent cGMP-mediated pulmonary
vasorelaxation (response to ACh). This impairment was attenuated with
IL-11 administration by 52% at 106 M ACh and by 77% with
TNFBP. As shown in Fig. 3, control rings were preconstricted to 277 ± 15 mg PE-induced tension and relaxed to 11 ± 4 mg tension with
10
6 M ACh. In LPS-treated
rats preconstricted to 274 ± 15 mg tension, 216 ± 16 mg
PE-induced tension remained in response to
10
6 M ACh
(P < 0.05 vs. control value). Rings
from (IL-11 plus LPS)-treated rats were preconstricted with PE to 298 ± 10 mg tension, with 104 ± 12 mg tension remaining in response
to 10
6 M ACh. Rings from
(TNFBP plus LPS)-treated rats were preconstricted with PE to 300 ± 21 mg tension, with 60 ± 17 mg tension remaining in response to
10
6 M ACh. Thus (IL-11 plus
LPS)- and (TNFBP plus LPS)-treated rats had an impaired response to ACh
compared with control rats (P < 0.05). However, pretreatment with IL-11 (or TNFBP) before LPS produced
markedly less dysfunction of cGMP-mediated pulmonary vasorelaxation in
response to ACh than that in LPS alone-treated rats
(P < 0.05).
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Endothelium-dependent, receptor-independent
cGMP- mediated pulmonary vasorelaxation (response to A-23187)
was significantly less impaired in (IL-11 plus LPS)-treated rats
compared with LPS alone-treated rats, with a 48% improved relaxation
response at 106 M A-23187
(Fig. 4). This same response was paralleled
with TNFBP treatment before LPS, with a 72% improvement in the
relaxation response at 10
6
M A-23187. Control rats were preconstricted to 303 ± 23 mg
PE-induced tension and relaxed to 11 ± 6 mg tension with
10
6 M A-23187. In
LPS-treated rats preconstricted to 281 ± 15 mg tension, 185 ± 26 mg PE-induced tension remained in response to 10
6 M A-23187
(P < 0.05 vs. control value). Rings
from (IL-11 plus LPS)-treated rats were preconstricted with PE to 304 ± 18 mg tension with 96 ± 9 mg tension remaining in response to
10
6 M A-23187. Rings from
(TNFBP plus LPS)-treated rats were preconstricted to 311 ± 17 mg,
with 51 ± 14 mg tension remaining in response to
10
6 M A-23187. Thus (IL-11
plus endotoxin)- or (TNFBP plus LPS)-treated rats had an
impaired response to A-23187 compared with control rats
(P < 0.05). However, [IL-11
(or TNFBP) plus LPS]-treated rats had significantly less
dysfunction of cGMP-mediated pulmonary vasorelaxation in response to
A-23187 than LPS alone-treated rats (P < 0.05).
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Endothelium-independent cGMP-mediated vasorelaxation by direct
stimulation of soluble guanylate cyclase (response to SNP) was less
impaired after IL-11 in LPS-treated rats (74%) compared with that in
LPS alone-treated rats only at the single concentration of
106 M. Again, this response
was paralleled with TNFBP treatment before LPS, with a similar 74%
improvement in the relaxation response at the same, single dose of SNP.
As shown in Fig. 5, control rings were
preconstricted to 298 ± 14 mg PE-induced tension and relaxed to 0 mg tension with 10
6 M SNP.
In LPS-treated rats preconstricted to 299 ± 24 mg tension, 53 ± 10 mg PE-induced tension remained in response to
10
6 M SNP
(P < 0.05 vs. control value). Rings
from (IL-11 plus LPS)-treated rats were preconstricted with PE to 306 ± 15 mg tension, with 14 ± 4 mg tension remaining in response
to 10
6 M SNP. Rings from
(TNFBP plus endotoxin)-treated rats were preconstricted with PE to 327 ± 22 mg tension, with 14 ± 7 mg tension remaining in response
to 10
6 M SNP. Thus
[IL-11 (or TNFBP) plus LPS]-treated rats had an improved relaxation response at the level of the smooth muscle after LPS treatment only at the single concentration of
10
5 M SNP
(P < 0.05).
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Survival study. As shown in Fig.
6, IL-11 attenuated LPS-induced mortality
in CF1 mice. The LPS-treated mice had a 90% mortality by 60 h.
Endotoxin-injected mice pretreated with IL-11 experienced an overall
mortality of 50% at 72 h, which did not change at 7 days. Survival
differences were stable after 60 h. Thus overall LPS lethality was
diminished by IL-11 treatment at 60 h
(P = 0.02) and was sustained through 7 days (P = 0.05).
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DISCUSSION |
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IL-11 is a member of the gp130 receptor subunit cytokine family; others
include IL-6, leukemic inhibitory factor, oncastatin-M, cardiotrophin-1, and ciliary neurotrophic factor (33). First discovered
in 1990, IL-11 has a variety of in vitro biological activities within
the hematopoietic, lymphopoietic, hepatic, adipose, bone,
gastrointestinal, and nervous systems (13, 48). In the present study,
pretreatment with IL-11 attenuated LPS-induced lung inflammation as
demonstrated by diminished pulmonary tissue TNF- levels and
neutrophil accumulation. This anti-inflammatory influence of IL-11 also
diminished pulmonary vasomotor dysfunction. Specifically, IL-11
attenuated LPS-induced dysfunction of endothelium-dependent and
-independent mechanisms of pulmonary vasorelaxation that require the
generation of cGMP. These findings suggest that IL-11 inhibits the
inflammatory cascade initiated by systemic LPS in the lung, with a
concomitant decrease in pulmonary vascular endothelial and smooth
muscle impairment. The effects of IL-11 also included reduced
LPS-induced mortality in mice.
Several investigators have demonstrated beneficial effects of IL-11 in
experimental sepsis. Pretreatment with IL-11 significantly reduced
mortality in a murine model of toxic shock syndrome (1) and in
experimental group B streptococcal sepsis in neonatal rats (5). In a
rabbit model of endotoxemia, IL-11 pretreatment prevented hypotension
and decreased gastrointestinal mucosal damage induced by LPS (30). The
anti-inflammatory effects of IL-11 on both murine and rabbit models of
endotoxemia appear to be due to inhibition of the production of
proinflammatory mediators. Trepicchio et al. (43) demonstrated that
IL-11 reduced circulating levels of proinflammatory cytokines such as
TNF-, IL-1
, and interferon-
after endotoxin administration in
a dose-dependent fashion in mice. Furthermore, these investigators
found that in vitro treatment of peritoneal macrophages with IL-11
before an endotoxin challenge decreased TNF-
production by 60%.
The results of the present study demonstrate that LPS increases lung
TNF- levels and lung neutrophil accumulation in rats. These findings
are associated with impairment of pulmonary vasorelaxation mechanisms
and histological endothelial injury (14, 36). After LPS treatment,
investigators (12, 17, 40) have observed increased steady-state levels
of TNF-
mRNA in the murine macrophage. TNF-
levels rise with
endotoxemia, with subsequent lung edema and neutrophil sequestration,
increased protein extravasation, and histological evidence of alveolar
damage in bovine and guinea pig models (19, 39). Other
investigators (27) observed that administration of TNF-
alone to guinea pigs results in lung injury as determined by increased
pulmonary arterial pressures, lung edema, and lung protein
permeability. Others (21, 27, 46) have observed in sheep, guinea pigs,
and rodents that TNF-
impairs endothelium-dependent mechanisms of
vasorelaxation in the aorta and pulmonary artery. In the present study,
pretreatment with TNFBP attenuated LPS-induced acute lung injury as
measured by lung neutrophil accumulation and impairment of the
mechanisms of cGMP-mediated pulmonary vasorelaxation. The present
results support the role of TNF-
as a mediator of LPS-induced lung
injury. The novel finding of this study is the observation that IL-11 appears to attenuate LPS-induced lung injury comparable to that of
TNFBP. IL-11 substantially decreases lung TNF-
levels 2 h after LPS
treatment. TNFBP and IL-11 similarly attenuate lung neutrophil
accumulation and impairment of cGMP-mediated mechanisms of pulmonary
vasorelaxation 6 h after LPS treatment. The data of the present study
suggest that IL-11 has anti-inflammatory effects in a rat model of
LPS-induced lung injury that may function through the attenuation or
downregulation of TNF-
production.
IL-11 is characterized as a member of the IL-6 superfamily of proteins
that share the gp130 transmembrane-receptor subunit. This superfamily
of proteins includes leukemic inhibitory factor, oncastatin-M,
cardiotrophin-1, and ciliary neurotrophic factor. The IL-6-receptor
complex is composed of two distinct transmembrane molecules:
1) a ligand-binding subunit (IL-6R)
and 2) a signal-transducing subunit
(gp130) (22). Some members of the IL-6 family (IL-6 and IL-11) induce
homodimerization of gp130 (20, 31), whereas others (leukemic inhibitory
factor, oncastatin-M, and ciliary neurotrophic factor) induce
heterodimerization, with the 190-kDa leukemic inhibitory factor
receptor (9). After dimerization, these receptors activate the
transcription factor nuclear factor-IL-6 via the Ras-mitogen-activated
protein kinase cascade and activate the Janus kinase-signal
transducer and activator of transcription signaling pathway (8, 23).
Anti-inflammatory effects of gp130 signaling extends to other cytokines
including IL-6. Leukemic inhibitory factor, cardiotrophin-1, and
ciliary neurotrophic factor appear to blunt the inflammatory response
after a stimulus. Specifically, pretreatment with these cytokines is
associated with attenuation of LPS-induced TNF- production (3, 4,
11, 35, 44). Whether IL-6 affords the same protection as IL-11 in acute
lung injury remains unclear. However, IL-6 inhibits TNF-
and IL-1 production by mononuclear cells in vitro and reduces TNF-
release in
endotoxemic mice in vivo (41, 45). The role of IL-6 in the pathogenesis
of endotoxin- or TNF-
-induced inflammation appears to be limited
(25, 26). Libert and colleagues (25, 26) found that IL-6
antibody and anti-IL-6-receptor antibody conferred protection to lethal
doses of TNF-
and LPS. However, both antibodies failed to protect
against higher doses of TNF-
and LPS. The anti-IL-6 antibody was
unable to protect against TNF-
in mice sensitized by galactosamine,
corticoid-receptor antagonist RU-38486, or human IL-1
. Furthermore,
protection did not correlate with serum concentrations of IL-6.
Alternative explanations for the LPS-attenuating effects of IL-11
include influences of IL-11 on circulating neutrophil counts, increased
LPS clearance, and/or immunomodulation secondary to the species
differences between the recombinant human IL-11 protein and the rodent
and murine models. IL-11 has well-described effects on bone marrow. It
appears that IL-11 acts synergistically with other early- and
late-acting growth factors to stimulate various stages and lineages of
hematopoiesis. IL-11 has been associated with megakaryocytopoiesis,
thrombocytopoiesis, and erythropoiesis (13). Although in vivo IL-11
increases the cycling rates and absolute myeloid progenitors in both
the bone marrow and spleen of normal mice (18), it has no effects on
peripheral leukocyte counts when administered to normal rodents (50)
and nonhuman primates (29). Increased LPS clearance could produce
results similar to those reported. It is currently unknown whether
IL-11 alters LPS clearance (i.e., upregulation of LPS binding protein, enhanced metabolism and/or excretion, and/or increased sequestration by
neutrophils and/or macrophages). Because IL-11 is a recombinant human
protein, it is theoretically possible that this cross-species exposure
induces an immunomodulatory effect observed as attenuated lung TNF-
and neutrophil sequestration and diminished pulmonary vascular
endothelial and smooth muscle injury.
The results of the present examination of LPS-induced lung injury contribute to the growing body of evidence that IL-11 is associated with attenuation of the inflammatory response. By blunting the proinflammatory response, IL-11 diminishes pulmonary vasomotor dysfunction in rats and ultimately improves survival in mice to a lethal LPS challenge.
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ACKNOWLEDGEMENTS |
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We thank Dr. John Ryan (Genetics Institute, Cambridge, MA) for the kind gift of interleukin-11 and Dr. Carl K. Edwards (Amgen, Boulder, CO) for providing the tumor necrosis factor binding protein.
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FOOTNOTES |
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This work was supported by an American College of Surgery Faculty Research grant (to R. C. MnIntyre, Jr.); National Heart, Lung, and Blood Institute Grant R29-HL-49398 (to D. A. Fullerton); and National Institute of Allergy and Infectious Diseases Grant AI-15614 (to C. A. Dinarello)
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. §1734 solely to indicate this fact.
Address for reprint requests and other correspondence: R. C. McIntyre, Jr., Dept. of Surgery, 4200 East Ninth Ave., Box C-313, Univ. of Colorado Health Sciences Center, Denver, CO 80262 (E-mail: robert.mcintyre{at}uchsc.edu).
Received 4 November 1998; accepted in final form 18 May 1999.
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