1 Section of Infectious Diseases, Department of Medicine, Baylor College of Medicine, Houston, Texas 77030; 2 University of Pittsburgh Cancer Institute, Pittsburgh 15213; and 3 Department of Surgery, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15213
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ABSTRACT |
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Interleukin-6 (IL-6) is produced within
multiple tissues and can be readily detected in the circulation in
resuscitated hemorrhagic shock (HS). Instillation of IL-6 into lungs of
normal rats induces polymorphonuclear neutrophilic granulocyte (PMN)
infiltration and lung damage, while infusion of IL-6 into the systemic
circulation of rats during resuscitation from HS reduces PMN
recruitment and lung injury. The current study was designed to
determine whether or not IL-6 makes an essential contribution to
postresuscitation inflammation and which of the two effects of IL-6,
its local proinflammatory effect or its systemic anti-inflammatory
effect, is dominant in HS. Wild-type and IL-6-deficient mice were
subjected to HS followed by resuscitation and death 4 h later.
IL-6-deficient mice subjected to HS did not demonstrate any features of
postresuscitation inflammation observed in wild-type mice, including
increased PMN infiltration into the lungs, increased alveolar
cross-sectional surface area, increased PMN infiltration into the
liver, increased liver necrosis, increased signal transducer and
activator of transcription 3 activation, and increased nuclear
factor-B activity. These findings indicate that IL-6 is an essential
component of the postresuscitation inflammatory cascade in HS and that
the local proinflammatory effects of IL-6 on PMN infiltration and organ
damage in HS dominate over the anti-inflammatory effects of systemic
IL-6.
signal transducers and activators of transcription proteins; nuclear factor-B; neutrophils; myeloperoxidase; alveolar wall
cross-sectional surface area; focal liver necrosis; interleukin-6
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INTRODUCTION |
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INTERLEUKIN-6 (IL-6)
is a 21-kDa cytokine that is produced by a variety of cells including
fibroblasts, endothelial cells, mononuclear phagocytes, neutrophils,
hepatocytes, and T and B lymphocytes. IL-6 receptor is composed of two
chains, an alpha chain (gp80; CD126) specific for IL-6, and a beta
chain (gp130) shared with all other members of the IL-6 family,
including IL-11, oncostatin M, leukemia inhibitory factor, ciliary
neurotrophic factor, and cardiotropin 1. IL-6R occurs as a
membrane-bound protein and in a soluble form. Soluble IL-6R
results
from alternative mRNA splicing or from C-reactive protein-controlled
cleavage of the membrane-bound receptor. Membrane-bound IL-6R
expression is cell type restricted, whereas gp130 expression is
ubiquitous. Soluble IL-6R
is detectable in the serum of normal
individuals; circulating levels of soluble IL-6R
increase in
inflammatory states. Unlike other soluble receptors, soluble IL-6R
is agonistic; consequently, in the presence of IL-6 and soluble
IL-6R
, virtually all cells become IL-6 responsive. IL-6 affects a
variety of biological functions, including immunoglobulin production,
the acute phase response, and inflammation. IL-6 has been shown to
contribute to polymorphonuclear neutrophilic granulocyte (PMN)
production in response to infection (9, 10) and to
contribute to activation of PMN effector functions (12,
21).
We have previously demonstrated that IL-6 mRNA and protein were produced in the lungs, liver, and intestinal tracts of rats subjected to resuscitated hemorrhagic shock (HS) (18, 19) and that both the ischemic and reperfusion phases of resuscitated HS were required for their production (18). To investigate the consequence of this local production of IL-6 on inflammation in HS, we instilled IL-6 into the lungs of normal rats and observed increased PMN infiltration and lung damage (19). Others have demonstrated elevated circulating levels of IL-6 in humans and animals following trauma and HS (16, 30). In contrast to the effects of local instillation of IL-6, we observed that systemic infusion of IL-6 reduced inflammation and injury in both organs.
To determine which of the two effects of IL-6, its local
proinflammatory effect or its systemic anti-inflammatory effect, is
dominant in HS, we examined the extent of PMN infiltration, organ
injury, and the activity levels of proinflammatory transcriptional factors in IL-6-deficient mice compared with wild-type mice.
IL-6-deficient mice subjected to HS did not demonstrate any features of
postresuscitation inflammation observed in wild-type mice, which
included increased PMN infiltration into the lungs, increased alveolar
cross-sectional surface area, increased PMN infiltration into the
liver, increased liver necrosis, increased signal transducers and
activators of transcription (STAT3) activation, and increased nuclear
factor (NF)-B activity. These findings indicate that IL-6 is an
essential component of the postresuscitation inflammatory cascade in HS and that the local proinflammatory effects of IL-6 on PMN infiltration and organ damage in HS dominate over the anti-inflammatory effects of
systemic IL-6.
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MATERIALS AND METHODS |
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Animals. Animal protocols were approved by the University of Pittsburgh Institutional Review Board for animal experimentation and were performed in accordance with the guidelines outlined by the National Institutes of Health for the care and use of laboratory animals. IL-6-deficient mice bred into the C57BL/6 background were generated as described (24) and generously provided by Dr. Valerie Poli (Univ. of Dundee). C57BL/6 mice were obtained from Charles River Laboratories (Southbridge, MA). Mice were bred in a specific pathogen-free animal barrier facility, maintained in standard conditions under a 12-h light-dark cycle, provided standard food and water ad libitum, and used at 8-10 wk of age.
HS protocol.
Wild-type and IL-6-deficient mice were randomly subjected to either the
HS or sham protocol as described (20). Briefly, mice were
anesthetized initially using intraperitoneal pentobarbital sodium (50 mg/kg). Both femoral arteries were surgically prepared and cannulated.
The left artery was used for continuous blood pressure monitoring. The
right artery was used for blood withdrawal and blood and fluid
administration. Animals were subjected to HS by withdrawal of blood
(2.25 ml/100 g body wt) over 10 min to achieve a mean arterial pressure
(MAP) of 30 mmHg. MAP was maintained at 30 mmHg for 3 h with
continuous monitoring of blood pressure and withdrawal and return of
blood as needed. Cannulas, syringes, and tubing were flushed with
heparin sodium (1,000 U/ml) before all procedures. The animals were
resuscitated to a MAP of 80 mmHg by administration of the remaining
shed blood plus intra-arterial injection of 1 ml of saline over 30 min.
Mice were killed by exsanguination 4 h after resuscitation.
Time-matched sham control animals underwent cannulation, anesthesia,
and monitoring procedures for an identical period of time as shock
animals but were not bled. There were six animals in each shock and
sham group.
Isolation and examination of lung and liver. After the mice were killed, the carcasses were flushed with cold (4°C) saline. The right lung was fixed with paraformaldehyde solution (4%) by inflation under a constant and fixed pressure (20 cm water). The left lung was frozen in liquid nitrogen. A portion of the liver was placed in paraformaldehyde (4%); another portion was frozen in liquid nitrogen. Paraformaldehyde-fixed specimens were sectioned and stained for myeloperoxidase (MPO) with hematoxylin and eosin (H+E) using standard procedures as described (17). The stained slides were examined at ×50-600 magnification. For quantitation of PMN infiltration, 10 randomly chosen (×400) fields of each lung and liver specimen stained with MPO were blindly scored for the number of intensely stained MPO-positive PMN as described (17).
Quantitation of alveolar wall cross-sectional surface area and focal liver necrosis. To quantitatively assess lung injury in sham and HS animals, we microscopically examined the H+E stained lung sections and measured the cross-sectional surface area of the alveoli. Five randomly chosen alveoli in each lung specimen were blindly measured by OPTIMAS identification techniques (Bioscan, Washington, DC) using a computer imaging device as described (25, 27). Images of the alveolar wall were optimized by adjusting contrast, gray scale, and exposure time and manually outlined for cross-sectional surface area quantitation. The same process was used to quantitate focal liver necrosis, except that the total area of focal liver necrosis on each slide section was measured and the area of focal liver necrosis was normalized for total area of liver examined.
Electrophoretic mobility shift assay.
Electrophoretic mobility shift assay (EMSA) was performed using whole
tissue extracts of frozen sections of liver as described (17). Briefly, binding reactions were performed using 20 µg of extracted protein and 32P-radiolabeled DNA binding
elements. EMSA was performed using a 4% of polyacrylamide gel. STAT3
activity was assessed using the hSIE (high-affinity serum-inducible
element) duplex oligonucleotide probe that is preferentially bound by
homodimers or heterodimers of STAT3 and STAT1 (31). The
mobility of the hSIE/STAT protein complex on EMSA gels depends on dimer
composition with STAT3 homodimers [serum-inducible factor (SIF)-A
complex] migrating slowest, STAT1 homodimers (SIF-C complex) migrating
fastest, and STAT3/STAT1 heterodimers (SIF-B complex) having
intermediate mobility. NF-B activity was determined by EMSA using a
32P-radiolabeled duplex oligonucleotide based on the
well-characterized NF-
B binding site within the murine inducible
nitric oxide synthase promoter (11). The level of
transcription factor activation of NF-
B and STAT3 were quantitated
using PhosphorImager analysis of the appropriate gel shift band as
described (17).
Statistical analysis. Data are presented as means ± SE. Differences within groups were determined using one-way ANOVA. Statistical significance of one-way ANOVA was assessed using Duncan's multiple range test.
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RESULTS |
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Effects of HS on lung PMN infiltration and injury.
We have previously shown that the lungs of rats harvested 4 h
after resuscitated HS exhibited increased inflammation and injury compared with sham-treated animals (17). Wild-type mice
subjected to HS also exhibited increased PMN infiltration and
lung injury compared with sham controls (Fig.
1), as evidenced by increased pneumocyte
swelling and infiltration of PMN into the interstitium and alveoli. In
contrast, PMN infiltration and lung injury were less evident in
IL-6-deficient mice subjected to HS (Fig. 1).
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Effects of HS on liver PMN infiltration and necrosis.
We previously demonstrated that HS caused liver damage measured by
increased plasma transaminase levels in rats and mice (17) and by extent of focal liver necrosis in rats (23). In the
current study, we demonstrate that the liver injury induced by HS in
wild-type mice also consists of focal hepatocellular necrosis (Fig.
4), which is accompanied by PMN
infiltration (Figs. 4 and 5). Wild-type mice subjected to HS demonstrated a 29-fold increase in liver PMN
infiltration compared with sham controls (P < 0.01),
whereas no significant difference in PMN infiltration was detected
between IL-6-deficient animals subjected to the sham and HS protocol. Similarly, quantitation of focal liver necrosis in
wild-type mice demonstrated a 58-fold increase in liver necrosis
compared with sham controls (P < 0.01), whereas no
significant difference was detected between IL-6-deficient sham and HS
groups (Fig. 6).
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IL-6 is the predominant cytokine contributing to STAT3 activation
in liver in HS.
IL-6 is a central cytokine regulating the acute phase response
of the liver. This effect is mediated, in part, through the activation
of STAT3 by IL-6. We have previously demonstrated rapid and concurrent
IL-6 production and STAT3 activation in liver of rats subjected to HS
(18, 19). Previous studies demonstrated markedly
diminished STAT3 activation in liver of IL-6-deficient mice following a
localized inflammatory stimulus (subcutaneous turpentine injection) but
near normal activation of STAT3 in liver of IL-6-deficient mice
following a systemic inflammatory stimulus (intraperitoneal injection
of bacterial lipopolysaccharide, LPS) (2). To directly
assess if IL-6 is an important mediator of STAT3 activation in liver in
HS, we measured STAT3 activity in whole liver extracts of wild-type and
IL-6-deficient mice following HS (Fig.
7). Although STAT3 activity in wild-type
mice subjected to HS was increased 35-fold over sham controls
(P < 0.01), STAT3 activity in IL-6-deficient mice was
not increased significantly in shock vs. sham animals, indicating that
IL-6 alone is sufficient to account for STAT3 activation in liver
following resuscitated HS.
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NF-B activation following HS is reduced in IL-6-deficient mice.
We have previously demonstrated that reduction of induced nitric oxide,
either pharmacologically in rats or genetically in mice, results in
decreased PMN recruitment and organ damage; this effect was mediated,
in part, by reduced NF-
B activity (17). To assess
whether or not the decrease in PMN infiltration and organ damage
observed in IL-6-deficient mice may be mediated through impaired
NF-
B activation, we measured NF-
B activity in liver extracts of
wild-type and IL-6-deficient mice following HS (Fig. 8). As observed previously in the lungs
of mice subjected to HS, HS induced a nearly threefold increase in
NF-
B activity in the liver compared with sham controls
(P < 0.05). In contrast, there was no increase in
NF-
B activity in livers of IL-6-deficient mice following HS compared
with sham controls (Fig. 8).
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DISCUSSION |
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Our findings demonstrate that compared with HS in wild-type mice,
HS in IL-6-deficient mice does not result in PMN infiltration into the
lung or liver and does not increase lung alveolar cross-sectional surface area or focal liver necrosis. In addition, similar to its role
in the acute phase response of liver in models of localized inflammation, IL-6 is the major mediator of STAT3 activation in liver
following HS. Finally, activation of NF-B was impaired in liver of
IL-6-deficient mice following HS, which may contribute to the impaired
inflammatory response seen in these animals.
Review of the literature on the role of IL-6 in inflammation suggests that the net effect of IL-6 on the host inflammatory response reflects a balance of two opposing effects, a paracrine effect of IL-6 that promotes inflammation, and an endocrine effect of IL-6 that diminishes inflammation. Previous studies with IL-6-deficient mice in infectious disease models demonstrated increased susceptibility to listeriosis (9, 22) and to infections with vaccinia virus (22), Escherichia coli (10), and Candida albicans. These studies indicated that IL-6 is an important component of the local inflammatory and immune response directed at limiting infection caused by a variety of infectious agents. In studies using noninfectious disease models and localized insults, IL-6-deficient mice demonstrated 1) a defective inflammatory response following subcutaneous injection of turpentine (13), 2) a defect in chemokine production resulting in diminished recruitment of neutrophils into tissue sites (26), 3) markedly reduced joint damage in a model of collagen-induced arthritis (3), and 4) resistance to splanchnic artery occlusion, a localized ischemic-reperfusion injury (8). In complementary types of studies, overexpression of IL-6 in the pancreas of transgenic mice promoted local inflammation (7) and instillation of IL-6 into the lungs of normal rats, resulting in lung inflammation and injury (19).
In addition to its local proinflammatory effects, several in vitro and
in vivo studies have shown that IL-6 has anti-inflammatory effects.
Exposure of cells to IL-6 or intraperitoneal injection of IL-6 was
demonstrated to inhibit tumor necrosis factor- (TNF-
) and IL-1
production in response to LPS and to protect against LPS toxicity,
respectively (1, 4, 32). IL-6 also completely protected
mice from mortality in a model of staphylococcal enterotoxin-induced toxic shock (5). We previously observed dramatically
diminished lung and liver inflammation and injury in rats subjected to
HS and resuscitated with fluids that contained IL-6 (23).
IL-6 administration to cancer patients increased circulating levels of
IL-1 receptor antagonist and soluble TNF-
receptor p55
(29). Overall, these findings are consistent with the role
of circulating IL-6 in downmodulating the inflammatory response,
especially in the setting of another local or systemic inflammatory insult.
Our findings reported here extend the findings of Cuzzocrea et al. (8) by demonstrating that IL-6 is essential not only for a localized ischemia-reperfusion injury but also a total body ischemia-reperfusion injury such as HS. In addition, our findings of reduced organ inflammation and injury in IL-6-deficient mice indicate that, in the case of HS, the local proinflammatory effects of endogenous IL-6 dominate over its systemic anti-inflammatory effects.
In a model of hepatic ischemia-reperfusion injury, Camargo et al.
(6) demonstrated that systemic infusion of IL-6 resulted in reduced mortality, reduced hepatic injury, and reduced hepatic production of C-reactive protein and TNF-, all consistent with an
anti-inflammatory role of IL-6 in this model of liver insult. However,
in contrast to our findings and those of Cuzzocrea et al.
(8), in IL-6-deficient mice, Camargo et al.
(6) demonstrated a small but significantly increased
hepatic injury in IL-6-deficient mice subjected to hepatic
ischemia-reperfusion injury. These results suggest that local
endogenous production of IL-6 by liver may be protective of liver
injury following a direct ischemia-reperfusion insult and raise the
possibility that local IL-6 production in the setting of direct liver
injury may serve predominantly an anti-inflammatory role.
IL-6 is the primary inducer of acute phase protein production by the liver in response to a variety of inflammatory insults (14). We have previously shown that STAT3 activation occurs in hepatocytes of Listeria-infected wild-type mice but not in IL-6-deficient mice and can be abrogated in wild-type mice by Kupffer cell depletion (15). Absence of acute phase protein production in IL-6-deficient mice following turpentine injection was accompanied by absence of STAT3 activation in the liver (2), supporting a critical role for STAT3 in acute phase protein production in response to a local inflammatory stimulus. Our finding of absent liver STAT3 activation in IL-6-deficient mice in HS indicates that IL-6 is the critical activator of STAT3 in HS. Studies are under way to determine whether or not upregulation of acute phase protein mRNA levels is also blunted in IL-6-deficient mice subjected to HS.
NF-B is a member of the Rel transcription family that is activated
in response to a variety of inflammatory stimuli including IL-1,
TNF-
, oxidative stress, ultraviolet and ionizing radiation, and LPS.
Activated NF-
B, in turn, transcriptionally activates a variety of
proinflammatory genes including granulocyte colony-stimulating factor
(G-CSF) and IL-6 (17, 28). Similar to IL-6-deficient mice,
we have previously demonstrated reduced lung and liver inflammation and
injury following HS in mice deficient in the gene for induced nitric
oxide; this reduction in inflammation and injury was accompanied by
reduced NF-
B activation and reduced G-CSF and IL-6 mRNA
(17). Examinations are under way to determine whether
impaired NF-
B activation in IL-6-deficient mice subjected to HS is
accompanied by diminished induction of proinflammatory cytokines, such
as G-CSF, and to determine whether or not physiological levels of IL-6
may be needed for normal levels of expression of components of the
NF-
B activation and signaling cascade.
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ACKNOWLEDGEMENTS |
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We are grateful to Jeffrey Baust for excellent technical assistance in the hemorrhagic shock protocol.
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FOOTNOTES |
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This work was supported by National Institutes of Health Grants GM-53789 and CA-72261.
Address for reprint requests and other correspondence: D. J. Tweardy, Section of Infectious Diseases, Baylor College of Medicine, One Baylor Plaza, BCM 286, Rm. N1319, Houston TX 77030 (E-mail: dtweardy{at}bcm.tmc.edu).
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.
Received 8 June 2000; accepted in final form 6 September 2000.
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REFERENCES |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
1.
Aderka, D,
Le JM,
and
Vilcek J.
IL-6 inhibits lipopolysaccharide-induced tumor necrosis factor production in cultured human monocytes, U937 cells and in mice.
J Immunol
143:
3517-3523,
1989
2.
Alonzi, T,
Fattori E,
Cappelletti M,
Ciliberto G,
and
Poli V.
Impaired Stat3 activation following localized inflammatory stimulus in IL-6-deficient mice.
Cytokine
10:
13-18,
1998[ISI][Medline].
3.
Alonzi, T,
Fattori E,
Lazzaro D,
Costa P,
Probert L,
Kollias G,
De Benedetti F,
Poli V,
and
Ciliberto G.
Interleukin 6 is required for the development of collagen-induced arthritis.
J Exp Med
187:
461-468,
1998
4.
Barton, BE,
and
Jackson JV.
Protective role of interleukin 6 in the lipopolysaccharide-galactosamine septic shock model.
Infect Immun
61:
1496-1499,
1993[Abstract].
5.
Barton, BE,
Shortall J,
and
Jackson JV.
Interleukins 6 and 11 protect mice from mortality in a staphylococcal enterotoxin-induced toxic shock model.
Infect Immun
64:
714-718,
1996[Abstract].
6.
Camargo, CA, Jr,
Madden JF,
Gao W,
Selvan RS,
and
Clavien PA.
Interleukin-6 protects liver against warm ischemia/reperfusion injury and promotes hepatocyte proliferation in the rodent.
Hepatology
26:
1513-1520,
1997[ISI][Medline].
7.
Campbell, IL,
Hobbs MV,
Dockter J,
Oldstone MB,
and
Allison J.
Islet inflammation and hyperplasia induced by the pancreatic islet-specific overexpression of interleukin-6 in transgenic mice.
Am J Pathol
145:
157-166,
1994[Abstract].
8.
Cuzzocrea, S,
De Sarro G,
Costantino G,
Ciliberto G,
Mazzon E,
De Sarro A,
and
Caputi AP.
IL-6 knock-out mice exhibit resistance to splanchnic artery occlusion shock.
J Leukoc Biol
66:
471-480,
1999[Abstract].
9.
Dalrymple, SA,
Lucian LA,
Slattery R,
McNeil T,
Aud DM,
Fuchino S,
Lee F,
and
Murray R.
Interleukin-6-deficient mice are highly susceptible to Listeria monocytogenes infection: correlation with inefficient neutrophilia.
Infect Immun
63:
2262-2268,
1995[Abstract].
10.
Dalrymple, SA,
Slattery R,
Aud DM,
Krishna M,
Lucian LA,
and
Murray R.
Interleukin-6 is required for a protective immune response to systemic Escherichia coli infection.
Infect Immun
64:
3231-3235,
1996[Abstract].
11.
De Vera, ME,
Geller DA,
and
Billiar TR.
Hepatic inducible nitric oxide synthase: regulation and function.
Biochem Soc Trans
23:
1008-1013,
1995[ISI][Medline].
12.
DiPersio, JF.
Colony-stimulating factors: enhancement of effector cell function.
Cancer Surv
9:
81-113,
1990[ISI][Medline].
13.
Fattori, E,
Cappelletti M,
Costa P,
Sellitto C,
Cantoni L,
Carelli M,
Faggioni R,
Fantuzzi G,
Ghezzi P,
and
Poli V.
Defective inflammatory response in interleukin 6-deficient mice.
J Exp Med
180:
1243-1250,
1994[Abstract].
14.
Gadient, RA,
and
Patterson PH.
Leukemia inhibitory factor, interleukin 6 and other cytokines using the GP130 transducing receptor: roles in inflammation and injury.
Stem Cells
17:
127-137,
1999
15.
Gregory, SH,
Wing EJ,
Danowski KL,
van Rooijen N,
Dyer KF,
and
Tweardy DJ.
IL-6 produced by Kupffer cells induces STAT protein activation in hepatocytes early during the course of systemic listerial infections.
J Immunol
160:
6056-6061,
1998
16.
Hamano, K,
Gohra H,
Noda H,
Katoh T,
Fujimura Y,
Zempo N,
and
Esato K.
Increased serum interleukin-8: correlation with poor prognosis in patients with postoperative multiple organ failure.
World J Surg
22:
1077-1081,
1998[ISI][Medline].
17.
Hierholzer, C,
Harbrecht B,
Menezes JM,
Kane J,
MacMicking J,
Nathan CF,
Peitzman AB,
Billiar TR,
and
Tweardy DJ.
Essential role of induced nitric oxide in the initiation of the inflammatory response after hemorrhagic shock.
J Exp Med
187:
917-928,
1998
18.
Hierholzer, C,
Kalff JC,
Bednarski B,
Memarzadeh F,
Kim YM,
Billiar TR,
and
Tweardy DJ.
Rapid and simultaneous activation of Stat3 and production of interleukin 6 in resuscitated hemorrhagic shock.
Arch Orthop Trauma Surg
119:
332-336,
1999[ISI][Medline].
19.
Hierholzer, C,
Kalff JC,
Omert L,
Tsukada K,
Loeffert JE,
Watkins SC,
Billiar TR,
and
Tweardy DJ.
Interleukin-6 production in hemorrhagic shock is accompanied by neutrophil recruitment and lung injury.
Am J Physiol Lung Cell Mol Physiol
275:
L611-L621,
1998
20.
Hierholzer, C,
Kelly E,
Tsukada K,
Loeffert E,
Watkins S,
Billiar TR,
and
Tweardy DJ.
Hemorrhagic shock induces G-CSF expression in bronchial epithelium.
Am J Physiol Lung Cell Mol Physiol
273:
L1058-L1064,
1997
21.
Johnson, JL,
Moore EE,
Tamura DY,
Zallen G,
Biffl WL,
and
Silliman CC.
Interleukin-6 augments neutrophil cytotoxic potential via selective enhancement of elastase release.
J Surg Res
76:
91-94,
1998[ISI][Medline].
22.
Kopf, M,
Baumann H,
Freer G,
Freudenberg M,
Lamers M,
Kishimoto T,
Zinkernagel R,
Bluethmann H,
and
Kohler G.
Impaired immune and acute-phase responses in interleukin-6-deficient mice.
Nature
368:
339-342,
1994[ISI][Medline].
23.
Meng, ZH,
Dyer K,
Billiar TR,
and
Tweardy DJ.
Distinct effects of systemic infusion of G-CSF versus IL-6 on lung and liver inflammation and injury in hemorrhagic shock.
Shock
14:
41-48,
2000[ISI][Medline].
24.
Poli, V,
Balena R,
Fattori E,
Markatos A,
Yamamoto M,
Tanaka H,
Ciliberto G,
Rodan GA,
and
Costantini F.
Interleukin-6 deficient mice are protected from bone loss caused by estrogen depletion.
EMBO J
13:
1189-1196,
1994[Abstract].
25.
Portet, S,
Vassy J,
Beil M,
Millot G,
Hebbache A,
Rigaut JP,
and
Schoevaert D.
Quantitative analysis of cytokeratin network topology in the MCF7 cell line.
Cytometry
35:
203-213,
1999[ISI][Medline].
26.
Romano, M,
Sironi M,
Toniatti C,
Polentarutti N,
Fruscella P,
Ghezzi P,
Faggioni R,
Luini W,
van Hinsbergh V,
Sozzani S,
Bussolino F,
Poli V,
Ciliberto G,
and
Mantovani A.
Role of IL-6 and its soluble receptor in induction of chemokines and leukocyte recruitment.
Immunity
6:
315-325,
1997[ISI][Medline].
27.
Sozmen, M,
Brown PJ,
and
Cripps PJ.
Quantitation of histochemical staining of salivary gland mucin using image analysis in cats and dogs.
Vet Res
30:
99-108,
1999[ISI][Medline].
28.
Thanos, D,
and
Maniatis T.
NF-B: a lesson in family values.
Cell
80:
529-532,
1995[ISI][Medline].
29.
Tilg, H,
Trehu E,
Atkins MB,
Dinarello CA,
and
Mier JW.
Induction of circulating interleukin 1 and interleukin 2 but not interleukin 6 immunotherapy.
Cytokine
7:
734-739,
1995[ISI][Medline].
30.
Toda, H,
Murata A,
Tanaka N,
Ohashi I,
Kato T,
Hayashida H,
Matsuura N,
and
Monden M.
Changes in serum granulocyte colony-stimulating factor (G-CSF) and interleukin 6 (IL-6) after surgical intervention.
Res Commun Mol Pathol Pharmacol
87:
275-286,
1995[ISI][Medline].
31.
Wagner, BJ,
Hayes TE,
Hoban CJ,
and
Cochran BH.
The SIF binding element confers sis/PDGF inducibility onto the c-fos promoter.
EMBO J
9:
4477-4484,
1990[Abstract].
32.
Yoshizawa, KI,
Naruto M,
and
Ida N.
Injection time of interleukin-6 determines fatal outcome in experimental endotoxin shock.
J Interferon Cytokine Res
16:
995-1000,
1996[ISI][Medline].