Departments of 1 Medicine and 2 Pharmacology and Toxicology, University of Louisville School of Medicine and 3 Department of Veterans Affairs Medical Center, Louisville, Kentucky 40292
![]() |
ABSTRACT |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
IL-10 is produced by a large variety of cells including monocytes, macrophages, B and T lymphocytes, as well as natural killer cells and is an important suppressor for both immunoproliferative and inflammatory responses. IL-10 exerts antifibrotic effects in the liver, and decreased monocyte synthesis of IL-10 is well documented in alcoholic cirrhosis. Intracellular deficiency of S-adenosylmethionine (AdoMet) is a hallmark of toxin-induced liver injury. Although the administration of exogenous AdoMet attenuates this injury, the mechanisms of its actions are not fully established. This study was performed to investigate the effect of exogenous AdoMet on IL-10 production in LPS-stimulated RAW 264.7 cells, a murine macrophage cell line. Our results demonstrated that exogenous AdoMet administration enhanced both protein production and gene expression of IL-10 in RAW 264.7 cells. Ethionine, an inhibitor for methionine adenosyltransferases, inhibited LPS-stimulated IL-10 both at the protein and mRNA levels. Exogenous AdoMet increased the intracellular cAMP concentration as early as 3 h and continued for 24 h after AdoMet treatment; however, the inhibitors for both adenylyl cyclase and PKA did not significantly affect IL-10 production. On the basis of these results, we conclude that AdoMet administration may exert its anti-inflammatory and hepatoprotective effects, at least in part, by enhancing LPS-stimulated IL-10 production.
inflammation; cytokines; liver injury
![]() |
INTRODUCTION |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
S-ADENOSYLMETHIONINE
(SAM, SAMe, or AdoMet) is produced from methionine and ATP by
methionine adenosyltransferase (MAT). AdoMet is a key intermediate in
the hepatic transsulfuration pathway and serves as a precursor for GSH
as well as a methyl donor in most transmethylation reactions (12,
22). Clinical studies have reported that administration of
stable salts of AdoMet has beneficial effects on many hepatic disorders
ranging from cholestasis to alcoholic liver disease (36).
Animal experiments have demonstrated that AdoMet has protective effects
against a variety of hepatotoxic agents, including carbon
tetrachloride, ethanol, and acetaminophen (4, 7, 20, 35).
These hepatotoxins induce hepatic deficiencies of AdoMet and GSH.
Although the mechanisms of its action are not fully established, one
potential beneficial effect of AdoMet is attenuation of proinflammatory
cytokine production by endotoxin (LPS)-stimulated monocytes/macrophages
(6). TNF- is a pleiotropic inflammatory cytokine and an
important mediator of toxin-induced liver injury (2, 9,
17). It has recently been shown (38) that AdoMet
supplementation to RAW 264.7, a murine macrophage cell line, decreases
the amount of TNF-
released in the conditioned medium and the
steady-state mRNA concentrations following LPS stimulation.
IL-10, initially named cytokine synthesis inhibitory factor, is an
important suppressor of both immunoproliferative and inflammatory responses (30, 33). Exogenous IL-10 downregulates
monocyte/macrophage effector functions including production of certain
proinflammatory cytokines such as TNF- and IL-1
(27). Inadequate monocyte production of IL-10 has been
postulated to play a role in increased TNF production and subsequent
liver injury in alcoholic liver disease (ALD) (18). In
addition, IL-10 may also exert antifibrotic effects in the liver
through inhibition of collagen gene transcription and increased
collagenase expression by hepatic stellate cells (37). The
effect(s) of AdoMet concentration (including exogenous administration
of AdoMet) on IL-10 production in monocytes have not been examined. In
the present study, we evaluated the effects of AdoMet both on IL-10
protein synthesis and gene expression in LPS-stimulated RAW cells.
![]() |
METHODS |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
Materials.
RAW 264.7 murine monocytes were obtained from the American Type Culture
Collection (ATCC, Manassas, VA). AdoMet, as its 1,4-butanedisulphonate salt, was provided by Drs. R. O'Brian (Knoll Pharmaceuticals, Piscataway, NJ) and G. Stramentionoli (Knoll Farmaceutici, Milan, Italy). LPS (Escherichia coli O111:B4) was purchased from
Difco Laboratories (Detroit, MI). Before use, LPS was dissolved in
sterile, pyrogen-free water, sonicated, and diluted with sterilized
HBSS. Penicillin, streptomycin, DMEM, trypsin, fetal bovine serum, and TRIzol reagent were purchased from Invitrogen (Grand Island, NY); 24- and 96-well plates were from Corning (Corning, NY); and murine IL-10,
TNF-, and cAMP ELISA kits were from Biosource International (Camarillo, CA). Purified hamster anti-mouse/rat TNF antibody, RiboQuant in vitro transcription kit, RiboQuant ribonuclease protection assay (RPA) kit, and mCK-2 RiboQuant mouse cytokine multi-probe template kit were from PharMingen (San Diego, CA). SQ 22536 and H-89
were from Calbiochem (San Diego, CA). All other reagents were of the
highest purity available and, unless indicated otherwise, were obtained
from Sigma (St. Louis, MO).
Cell culture. RAW 264.7 cells were cultured in DMEM containing 10% (vol/vol) fetal bovine serum, 2 mM glutamine, 5 U/ml penicillin, and 50 µg/ml streptomycin at 37°C in a humidified O2/CO2 (19:1) atmosphere.
3-(4,5-dimethythiazol-2-yl)-2,5-diphenyltetrazolium bromide assay. The cell viability was assessed by examining cell number with the 3-(4,5-dimethythiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. After treatments, cells were washed twice with PBS; then cell culture medium was removed, and serum-free medium containing 1 mg/ml MTT was added to the cells. After a 2-h incubation, 100 µl lysis buffer containing 20% SDS and 50% N,N-dimethyformamide were added and incubated at 37°C overnight. The optical density values were read at 570 nm.
HPLC assay for intracellular AdoMet. The intracellular concentrations of AdoMet and S-adenosylhomocysteine (SAH) were assayed by reverse-phase HPLC with deprotenized extracts of cells by a modified method of Merali et al. (25). Cell pellets were mixed with 0.25 ml of 4% metaphosphoric acid (MPA) and centrifuged at 10,000 g for 2 min. The supernatants were collected for HPLC analysis. The HPLC system was equipped with a Waters 501 pump, a manual injector, and a 5-µm Hypersil C18 reverse-phase column (250 × 4.6 mm). The mobile phase consisted of 40 mM ammonium phosphate, 8 mM heptane sulfonic acid (ion-pairing reagent), and 6% acetonitrile (pH 5.0) and it was run isocratically at a constant rate of 1.0 ml/min. AdoMet and SAH were detected using a Waters 740 detector at 254 nm. Standard solutions of AdoMet and SAH were prepared in 4% MPA. An internal standard, S-adenosylethionine (SAE), was added to all samples and standard solutions to a concentration of 100 nmol/ml. Protein concentrations were measured by a protein assay kit from BioRad in accordance with the manufacturer's instructions.
ELISA assay for IL-10, TNF-, and cAMP.
IL-10 and TNF-
in conditioned medium and cAMP were quantified using
ELISA kits in accordance with the manufacturer's instructions. The
detection limitation for IL-10 and TNF-
is 4.0 and 13.5 pg/ml, respectively, and the limit for cAMP is 0.39 pmol/ml. Whereas samples
for IL-10 assay were run undiluted, samples for TNF-
and cAMP were
fivefold diluted. All assays were run in triplicate.
RPA of IL-10 mRNA. Total RNA was isolated with TRIzol reagent (GIBCO-BRL) in accordance with the manufacturer's instructions. IL-10 mRNA was assayed by RPA using RiboQuant multiprobe RNase protection system according to the manufacturer's manual. Briefly, [32P]UTP-labeled RNA probe was prepared by in vitro transcription using multiprobe template set using mCK-2 as a template. Five to ten picograms of total RNA samples were hybridized overnight with purified RNA probe, after which free probe and other single-stranded RNA were digested with RNase A and T1 mix. The remaining RNase-protected probes were purified, resolved on 5% denaturating polyacrylamide gels, and quantitated by autoradiography.
Statistical analyses. All data are expressed as means ± SD. Statistical analysis was performed using one-way ANOVA and further analyzed by Newman-Keuls test for statistical difference. Differences between treatments were considered to be statistically significant at P < 0.05.
![]() |
RESULTS |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
Effects of AdoMet treatment on intracellular AdoMet concentration.
The effects of exogenous AdoMet treatment of RAW cells on intracellular
concentrations of AdoMet are shown in Fig.
1. The basal concentration of AdoMet in
RAW cells was 912.36 ± 253.6 pmol/mg protein and remained
unchanged during the culture conditions used in these experiments.
Treatment with 1 mM exogenous AdoMet resulted in a threefold elevation
of intracellular AdoMet concentrations within 2 h of exposure.
These levels remained elevated over 8 h.
|
Effects of AdoMet treatment on the release of IL-10 by LPS
stimulated RAW cell.
The effect of exogenous AdoMet on IL-10 production by macrophages was
determined by pretreating RAW cells with AdoMet for 2 h and then
stimulating with LPS. After a number of preliminary studies in which
the pretreatment period with AdoMet was varied from a few minutes to
overnight, we designed this protocol to optimize the changes in
LPS-stimulated IL-10 release by RAW cells without affecting their
viability. Figure 2 summarizes the dose response of AdoMet-enhanced IL-10 release into the conditioned medium.
Cells treated with 100 µM AdoMet demonstrated a significant increase
in IL-10 production following stimulation by LPS. When the cells were
pretreated with 1 mM AdoMet for 2 h, IL-10 production was
increased to ~200% of that of control cells by 16 h after LPS
stimulation. IL-10 production could not be detected in either untreated
cells or those treated with 1 mM AdoMet without LPS (data not shown).
The viability of these cells, measured by the conversion of MTT to
formazan, was unaffected by concentrations of AdoMet up to 1 mM (>90%
viability). Treatment of cells with higher concentrations of AdoMet
(e.g., 3 mM), however, significantly lowered cellular viability to
~70% (data not shown).
|
Time course changes of LPS-stimulated IL-10 release in the absence
or presence of 1 mM AdoMet.
In the control cells (no AdoMet), IL-10 levels demonstrated a
time-dependent increase during the 24-h culture period (from 34.99 ± 9.9 pg/ml in 2 h to 635.65 ± 48.45 pg/ml in 24 h)
after LPS stimulation (Fig. 3). Compared
with control cells, AdoMet-treated cells produced a higher level of
IL-10 by 8 h after LPS stimulation. By 24 h after LPS
stimulation, IL-10 production by AdoMet-treated cells reached almost
twice that in control cells (635.65 ± 48.45 pg/ml in control
cells vs. 1,113.53 ± 85.49 pg/ml in AdoMet-treated cells).
|
Effects of AdoMet and anti-IL-10 antibody on LPS-stimulated TNF production. As expected, exogenous AdoMet (2 mM) inhibited TNF production by >50% (23 ± 0.8 pg/ml in LPS treatment vs. 11.9 ± 1.3 pg/ml in AdoMet + LPS treatment) at 18 h after LPS stimulation. Pretreatment with anti-IL-10 antibody (10 µg/ml) modestly but significantly attenuated the TNF inhibitory effects of AdoMet (15.4 ± 0.6 pg/ml).
Effect of Ethionine and cycloleucine on IL-10 production by
LPS-stimulated RAW cells.
Ethionine is a competitive inhibitor of methyltransferases and induces
a functional AdoMet deficiency. To evaluate whether AdoMet deficiency
may inhibit LPS-stimulated IL-10 production, 3 mM ethionine was added
2 h before LPS stimulation. The time course of changes of IL-10
release into the media was monitored. Compared with control cells (no
ethionine), ethionine-treated cells demonstrated significantly
decreased IL-10 production, and this effect was present across a time
course from 4 to 24 h after LPS stimulation (Fig.
4). More than 75% of IL-10 production
elicited by LPS was inhibited by ethionine treatment. The viability of RAW cells was not affected by treatment with 3 mM ethionine (viability >90%). Cycloleucine also induces functional AdoMet deficiency (inhibits nonhepatic MAT activity). Cycloleucine at 20 and 40 mM
significantly decreased LPS-stimulated IL-10 production by 24 and 47%,
respectively. Adding AdoMet significantly reversed the cycloleucine
inhibition (data not shown).
|
Effects of exogenous AdoMet and ethionine on LPS-induced IL-10 gene
expression.
RPAs were performed to determine whether the effects of AdoMet and
ethionine on IL-10 expression could be attributed to changes in IL-10
mRNA levels following exposure to LPS. IL-10 mRNA was detected 4 h
after stimulation in both control (LPS alone) and AdoMet-treated cells,
but AdoMet-treated cells expressed higher levels of IL-10 mRNA than
control cells (Fig. 5). Whereas it was undetectable at 24 h in control cells, IL-10 mRNA expression in AdoMet-treated cells was prolonged to at least 24 h after
stimulation. Ethionine-treated cells expressed lower amounts of IL-10
mRNA than either control or AdoMet-treated cells by 8 h after
LPS-stimulation, and IL-10 mRNA returned to undetectable levels in
24 h after stimulation.
|
Role of cAMP pathway in the elevation of IL-10 production.
The effect of exogenous AdoMet on cytosolic cAMP concentrations in
macrophages was determined by ELISA, and the results are summarized in
Fig. 6. Cells treated with 1 mM AdoMet
showed an increase in intracellular cAMP concentrations from a basal
value of 8.84 ± 1.35 to 14.08 ± 0.78 pg/mg protein at
3 h. Intracellular levels of cAMP in AdoMet-treated cells remained
significantly elevated for 24 h. To investigate whether the
enhancement of IL-10 by AdoMet treatment resulted from increased
intracellular cAMP concentration, the inhibitors for adenylyl cyclase
and PKA were added to the medium before AdoMet administration, and the
results are shown in Fig. 7. Either 1 mM
SQ 22536 (inhibitor of adenylyl cyclase) or 1 µM H-89 (inhibitor of
PKA) was added to the medium 2 h before AdoMet administration, and
LPS was added 2 h later. AdoMet treatment elevated LPS-stimulated
IL-10 production significantly. SQ 22536 pretreatment did not change
the enhancement of IL-10 by AdoMet administration, whereas H-89 lowered
the enhancement slightly.
|
|
![]() |
DISCUSSION |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
IL-10 is a critical anti-inflammatory cytokine that inhibits the synthesis of proinflammatory cytokines in monocytes, macrophages, lymphocytes, and neutrophils (33). Exogenous administration of IL-10 has been shown to be hepatoprotective in multiple experimental models of liver injury such as LPS + galactosamine (28), C. parvum + LPS (32), and concanavalin A (Con A) (15). Exogenous IL-10 has also been used to decrease fibrosis in hepatitis C patients who are nonresponders to interferon therapy (29) and to control the inflammatory response during localized inflammation such as rheumatoid arthritis or systemic inflammation such as sepsis (8). With the use of IL-10 knockout mice, IL-10 has been shown to inhibit neutrophil infiltration and fibrosis in a carbon tetrachloride model of liver injury (21). Similarly, IL-10 knockout mice were shown to be more sensitive to acetaminophen hepatoxicity, demonstrating the importance of endogenous anti-inflammatory pathways in attenuating toxin/xenobiotic-induced hepatoxicity (3). Lastly, IL-10 knockout mice were shown to be more sensitive to alcohol-induced liver injury in a model of alcohol + LPS hepatoxicity (14).
Patients with alcoholic cirrhosis have a well-characterized decrease in LPS-stimulated IL-10 production (18, 34). In vitro studies have suggested that decreased IL-10 production plays a major role in the dysregulated TNF metabolism observed in ALD (18). Patients with ALD have a significantly higher incidence of an IL-10 polymorphism (13). Mice chronically fed alcohol have decreased LPS-stimulated IL-10 production in conjunction with increased liver injury (14). Similarly, incubation of a macrophage cell line with alcohol on a chronic basis causes decreased LPS-stimulated IL-10 production (34). Thus there is substantial evidence implicating inadequate IL-10 levels in many types of experimental and clinical liver disease, and there is an emerging rationale for exogenous IL-10 therapy or therapy with drugs that increase endogenous IL-10 in these liver diseases.
Subnormal hepatic AdoMet levels have been reported in various
experimental models of liver injury, and AdoMet therapy in rats attenuates liver injury due to cholestasis, ethanol, carbon
tetrachloride, fatty liver, acetaminophen, or galactosamine (7,
20, 35, 36). Liver-specific MAT knockout mice are highly
susceptible to another "stress" such as a choline-deficient diet
and develop fatty liver and periportal inflammation (23).
MAT deficiency modulates the expression of many genes, especially those
involved in proliferation and growth, and normal MAT activity appears
to be important for maintaining the hepatocyte in a
"differentiated" state. AdoMet downregulates production of the
cytotoxic proinflammatory cytokine TNF- in animal models of liver
injury and in peripheral blood monocytes or macrophage cell lines in
vitro (6, 38).
Patients with alcoholic cirrhosis who were randomized to receive AdoMet (1,200 mg/day orally) for 2 yr had decreased mortality/liver transplantation (16 vs. 30%) compared with the placebo-treated group (24). AdoMet has also been used successfully in various types of cholestatic liver disease (19). Thus there are animal studies and emerging clinical data indicating that AdoMet may be useful in several forms of liver disease.
In this study, we show that exogenous AdoMet enhanced LPS-induced IL-10 production in cultured RAW cells in a time- and dose-response fashion. Supplementation of RAW cells with AdoMet also increased IL-10 mRNA in response to LPS. Ethionine, which is converted to SAE, induces functional AdoMet deficiency. AdoMet deficiency induced by ethionine administration decreased IL-10 mRNA and protein secretion. Similarly, cycloleucine (which blocks extrahepatic MAT activity) also significantly inhibited LPS-stimulated IL-10 production. Thus, in this cell line widely used to study cytokine metabolism, it appears that AdoMet concentrations critically regulate LPS-stimulated IL-10 production. AdoMet also inhibits TNF production. With the use of anti-IL-10 antibody, we showed that a small, but significant, component of AdoMet's anti-TNF activity may be mediated through enhanced IL-10 production.
Data on whether or not AdoMet can be taken up intact by cells are still controversial (10, 39). We observed an approximately threefold increase in intracellular AdoMet concentration after supplementation with 1 mM exogenous AdoMet, although we did not examine the mechanisms by which this increase occurred. Such an increase could have resulted from either a change in its endogenous metabolism or from cellular uptake of the exogenous AdoMet.
There are multiple potential mechanisms whereby exogenous AdoMet may increase LPS-stimulated IL-10, with one possibility being increased cAMP. The anti-inflammatory functions of cAMP-elevating agents have been demonstrated in several cell systems including inhibition of TNF synthesis and enhancement of IL-10 synthesis both in human and murine monocytes. Previous studies (1, 5, 26, 31) reported that dibutyryl cAMP, an exogenous cAMP, upregulated IL-10 production both in LPS-stimulated human monocytes and Con A-stimulated CD8+ T cell clones. Drugs that elevate intracellular cAMP (e.g., iloprost, pentoxifylline, prostaglandin E2) augmented LPS-induced IL-10 production both at the protein and mRNA levels in human monocytes (11, 16). We demonstrated for the first time that supplementation of exogenous AdoMet to RAW cells increased intracellular cAMP concentrations as early as 3 h after AdoMet treatment. To investigate whether enhancement of IL-10 production in RAW cells treated with AdoMet involved the cAMP pathway, inhibitors for both adenylyl cyclase and PKA were used. Inhibition of adenylyl cyclase had no effect on IL-10 production, whereas the inhibition of PKA lowered IL-10 production only slightly. Thus, although the cAMP levels increased, it seems unlikely that the cAMP pathway plays a major role in the enhancement of LPS-induced IL-10 production in RAW cells treated with AdoMet.
In conclusion, this research demonstrates that AdoMet concentrations critically regulate LPS-stimulated IL-10 production in monocytes and that AdoMet elevated protein synthesis and gene expression of IL-10 in LPS-stimulated RAW cells. Although the focus of our research and this discussion has been on liver disease, the implications of this work extend far beyond hepatic diseases to other processes ranging from sepsis to rheumatoid arthritis, where modulation of IL-10 appears to play an important role in disease activity/progression.
![]() |
ACKNOWLEDGEMENTS |
---|
This research was supported by National Institute on Alcohol Abuse and Alcoholism Grants AA-01762 (to C. McClain), AA-10496 (to C. McClain), AA-00190 (to T. Chen), AA-00205 (to S. Barve), AA-00297 (to D. Hill), and AA-014085 (to D. Hill), a Kentucky Science and Engineering Foundation grant (to C. McClain), and by the Department of Veterans Affairs.
![]() |
FOOTNOTES |
---|
Address for reprint requests and other correspondence: C. McClain, Professor and Vice Chair, Dept. of Medicine, Univ. of Louisville Medical Center, Louisville, KY 40292 (E-mail: craig.mcclain{at}louisville.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.
10.1152/ajpgi.00426.2002
Received 3 October 2002; accepted in final form 6 February 2003.
![]() |
REFERENCES |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
1.
Arai, T,
Hiromatsu K,
Kobayashi N,
Takano M,
Ishida H,
Nimura Y,
and
Yoshikai Y.
IL-10 is involved in the protective effect of dibutyryl cyclic adenosine monophosphate on endotoxin-induced inflammatory liver injury.
J Immunol
155:
5743-5749,
1995[Abstract].
2.
Blazka, ME,
Wilmer JL,
Holladay SD,
Wilson RE,
and
Luster MI.
Role of proinflammatory cytokines in acetaminophen hepatotoxicity.
Toxicol Appl Pharmacol
133:
43-52,
1995[ISI][Medline].
3.
Bourdi, M,
Masubuchi Y,
Reilly TP,
Amouzadeh HR,
Martin JL,
George JW,
Shah AG,
and
Pohl LR.
Protection against acetaminophen-induced liver injury and lethality by interleukin 10: role of inducible nitric oxide synthase.
Hepatology
35:
289-298,
2002[ISI][Medline].
4.
Bray, GP,
Tredger JM,
and
Williams R.
S-adenosylmethionine protects against acetaminophen hepatotoxicity in two mouse models.
Hepatology
15:
297-301,
1992[ISI][Medline].
5.
Burchiel, SW,
Hanson K,
and
Warner NL.
Clonal heterogeneity of cyclic AMP responsiveness: a comparison of malignant murine lymphoid cell lines.
Int J Immunopharmacol
6:
35-42,
1984[ISI][Medline].
6.
Chawla, RK,
Watson WH,
Eastin CE,
Lee EY,
Schmidt J,
and
McClain CJ.
S-adenosylmethionine deficiency and TNF- in lipopolysaccharide-induced hepatic injury.
Am J Physiol Gastrointest Liver Physiol
275:
G125-G129,
1998
7.
Corrales, F,
Gimenez A,
Alvarez L,
Caballeria J,
Pajares MA,
Andreu H,
Pares A,
Mato JM,
and
Rodes J.
S-adenosylmethionine treatment prevents carbon tetrachloride-induced S-adenosylmethionine synthetase inactivation and attenuates liver injury.
Hepatology
16:
1022-1027,
1992[ISI][Medline].
8.
Cuzzocrea, S,
Mazzon E,
Dugo L,
Serraino I,
Britti D,
De Maio M,
and
Caputi AP.
Absence of endogeneous interleukin-10 enhances the evolution of murine type-II collagen-induced arthritis.
Eur Cytokine Netw
12:
568-580,
2001[ISI][Medline].
9.
DeCicco, LA,
Rikans LE,
Tutor CG,
and
Hornbrook KR.
Serum and liver concentrations of tumor necrosis factor alpha and interleukin-1 following administration of carbon tetrachloride to male rats.
Toxicol Lett
98:
115-121,
1998[ISI][Medline].
10.
Engstrom, MA,
and
Benevenga NJ.
Rates of oxidation of the methionine and S-adenosylmethionine methyl carbons in isolated rat hepatocytes.
J Nutr
117:
1820-1826,
1987[ISI][Medline].
11.
Fedyk, ER,
Adawi A,
Looney RJ,
and
Phipps RP.
Regulation of IgE and cytokine production by cAMP: implications for extrinsic asthma.
Clin Immunol Immunopathol
81:
101-113,
1996[ISI][Medline].
12.
Giulidori, P,
Galli-Kienle M,
Catto E,
and
Stramentinoli G.
Transmethylation, transsulfuration, and aminopropylation reactions of S-adenosyl-L-methionine in vivo.
J Biol Chem
259:
4205-4211,
1984
13.
Grove, J,
Daly AK,
Bassendine MF,
Gilvarry E,
and
Day CP.
Interleukin 10 promoter region polymorphisms and susceptibility to advanced alcoholic liver disease.
Gut
46:
540-545,
2000
14.
Hill, DB,
D'Souza NB,
Lee EY,
Burikhanov R,
Deaciuc IV,
and
de Villiers WJ.
A role for interleukin-10 in alcohol-induced liver sensitization to bacterial lipopolysaccharide.
Alcohol Clin Exp Res
26:
74-82,
2002[ISI][Medline].
15.
Kato, M,
Ikeda N,
Matsushita E,
Kaneko S,
and
Kobayashi K.
Involvement of IL-10, an anti-inflammatory cytokine in murine liver injury induced by concanavalin A.
Hepatol Res
20:
232-243,
2001[ISI][Medline].
16.
Khan, MM,
Sansoni P,
Engleman EG,
and
Melmon KL.
Pharmacologic effects of autacoids on subsets of T cells. Regulation of expression/function of histamine-2 receptors by a subset of suppressor cells.
J Clin Invest
75:
1578-1583,
1985[ISI][Medline].
17.
Khoruts, A,
Stahnke L,
McClain CJ,
Logan G,
and
Allen JI.
Circulating tumor necrosis factor, interleukin-1 and interleukin-6 concentrations in chronic alcoholic patients.
Hepatology
13:
267-276,
1991[ISI][Medline].
18.
Le Moine, O,
Marchant A,
De Groote D,
Azar C,
Goldman M,
and
Deviere J.
Role of defective monocyte interleukin-10 release in tumor necrosis factor- overproduction in alcoholic cirrhosis.
Hepatology
22:
1436-1439,
1995[Medline].
19.
Lieber, CS.
Role of S-adenosyl-L-methionine in the treatment of liver diseases.
J Hepatol
30:
1155-1159,
1999[ISI][Medline].
20.
Lieber, CS,
Casini A,
DeCarli LM,
Kim CI,
Lowe N,
Sasaki R,
and
Leo MA.
S-adenosyl-L-methionine attenuates alcohol-induced liver injury in the baboon.
Hepatology
11:
165-172,
1990[ISI][Medline].
21.
Louis, H,
Van Laethem JL,
Wu W,
Quertinmont E,
Degraef C,
Van den Berg K,
Demols A,
Goldman M,
Le Moine O,
Geerts A,
and
Deviere J.
Interleukin-10 controls neutrophilic infiltration, hepatocyte proliferation, and liver fibrosis induced by carbon tetrachloride in mice.
Hepatology
28:
1607-1615,
1998[ISI][Medline].
22.
Lu, SC
S-adenosylmethionine.
Int J Biochem Cell Biol
32:
391-395,
2000[ISI][Medline].
23.
Lu, SC,
Alvarez L,
Huang ZZ,
Chen L,
An W,
Corrales FJ,
Avila MA,
Kanel G,
and
Mato JM.
Methionine adenosyltransferase 1A knockout mice are predisposed to liver injury and exhibit increased expression of genes involved in proliferation.
Proc Natl Acad Sci USA
98:
5560-5565,
2001
24.
Mato, JM,
Camara J,
Fernandez de Paz J,
Caballeria L,
Coll S,
Caballero A,
Garcia-Buey L,
Beltran J,
Benita V,
Caballeria J,
Sola R,
Moreno-Otero R,
Barrao F,
Martin-Duce A,
Correa JA,
Pares A,
Barrao E,
Garcia-Magaz I,
Puerta JL,
Moreno J,
Boissard G,
Ortiz P,
and
Rodes J.
S-adenosylmethionine in alcoholic liver cirrhosis: a randomized, placebo-controlled, double-blind, multicenter clinical trial.
J Hepatol
30:
1081-1089,
1999[ISI][Medline].
25.
Merali, S,
Vargas D,
Franklin M,
and
Clarkson AB, Jr.
S-adenosylmethionine and Pneumocystis carinii.
J Biol Chem
275:
14958-14963,
2000
26.
Minai, Y,
Goto M,
Kohyama M,
Hisatsune T,
Nishijima KI,
and
Kaminogawa S.
Difference in signal transduction for IL-10 and IFN-gamma production in a CD8+ T cell clone.
Cell Immunol
172:
200-204,
1996[ISI][Medline].
27.
Moore, KW,
O'Garra A,
de Waal Malefyt R,
Vieira P,
and
Mosmann TR.
Interleukin-10.
Annu Rev Immunol
11:
165-190,
1993[ISI][Medline].
28.
Nagaki, M,
Tanaka M,
Sugiyama A,
Ohnishi H,
and
Moriwaki H.
Interleukin-10 inhibits hepatic injury and tumor necrosis factor- and interferon-
mRNA expression induced by staphylococcal enterotoxin B or lipopolysaccharide in galactosamine-sensitized mice.
J Hepatol
31:
815-824,
1999[ISI][Medline].
29.
Nelson, DR,
Lauwers GY,
Lau JY,
and
Davis GL.
Interleukin-10 treatment reduces fibrosis in patients with chronic hepatitis C: a pilot trial of interferon nonresponders.
Gastroenterology
118:
655-660,
2000[ISI][Medline].
30.
O'Garra, A,
Chang R,
Go N,
Hastings R,
Haughton G,
and
Howard M.
Ly-1 B (B-1) cells are the main source of B cell-derived interleukin-10.
Eur J Immunol
22:
711-717,
1992[ISI][Medline].
31.
Platzer, C,
Meisel C,
Vogt K,
Platzer M,
and
Volk HD.
Up-regulation of monocytic IL-10 by tumor necrosis factor- and cAMP elevating drugs.
Int Immunol
7:
517-523,
1995[Abstract].
32.
Smith, SR,
Terminelli C,
Denhardt G,
Narula S,
and
Thorbecke GJ.
Administration of interleukin-10 at the time of priming protects Corynebacterium parvum-primed mice against LPS- and TNF--induced lethality.
Cell Immunol
173:
207-214,
1996[ISI][Medline].
33.
Suda, T,
O'Garra A,
MacNeil I,
Fischer M,
Bond MW,
and
Zlotnik A.
Identification of a novel thymocyte growth-promoting factor derived from B cell lymphomas.
Cell Immunol
129:
228-240,
1990[ISI][Medline].
34.
Szuster-Ciesielska, A,
Daniluk J,
and
Kandefer-Zerszen M.
Serum levels of cytokines in alcoholic liver cirrhosis and pancreatitis.
Arch Immunol Ther Exp (Warsz)
48:
301-307,
2000[Medline].
35.
Varela-Moreiras, G,
Alonso-Aperte E,
Rubio M,
Gasso M,
Deulofeu R,
Alvarez L,
Caballeria J,
Rodes J,
and
Mato JM.
Carbon tetrachloride-induced hepatic injury is associated with global DNA hypomethylation and homocysteinemia: effect of S-adenosylmethionine treatment.
Hepatology
22:
1310-1315,
1995[Medline].
36.
Vendemiale, G,
Altomare E,
Trizio T,
Le Grazie C,
Di Padova C,
Salerno MT,
Carrieri V,
and
Albano O.
Effects of oral S-adenosyl-L-methionine on hepatic glutathione in patients with liver disease.
Scand J Gastroenterol
24:
407-415,
1989[ISI][Medline].
37.
Wang, SC,
Ohata M,
Schrum L,
Rippe RA,
and
Tsukamoto H.
Expression of interleukin-10 by in vitro and in vivo activated hepatic stellate cells.
J Biol Chem
273:
302-308,
1998
38.
Watson, WH,
Zhao Y,
and
Chawla RK.
S-adenosylmethionine attenuates the lipopolysaccharide-induced expression of the gene for tumor necrosis factor-.
Biochem J
342:
21-25,
1999[ISI][Medline].
39.
Zappia, V,
Galletti P,
Porcelli M,
Ruggiero G,
and
Andreana A.
Uptake of adenosylmethionine and related sulfur compounds by isolated rat liver.
FEBS Lett
90:
331-335,
1978[ISI][Medline].
HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
Visit Other APS Journals Online |