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Department of Internal Medicine, Shiga University of Medical Science, Seta Tukinowa, Otsu, Japan
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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B was assessed by EMSA. The
activation of mitogen-activated protein kinase (MAPK) was assessed by
immunoblotting. IL-6 secretion was rapidly induced by IL-17, IL-1
,
and TNF-
. EMSAs demonstrated that IL-17, IL-1, and TNF-
induced NF-B activation within 1.5 h after stimulation, and a
blockade of NF-B activation by the pyrrolidine derivative of
dithiocarbamate and tosyl-phe-chloromethylketone markedly reduced the
IL-17-, IL-1-, or TNF--induced IL-6 gene expression. Furthermore,
IL-17, IL-1, and TNF- induced a rapid activation of extracellular
signal-related kinase p42/44 and p38 MAPKs, and specific MAPK
inhibitors (SB203580, PD98059, and U0216) significantly reduced IL-17-,
IL-1-, or TNF--induced IL-6 secretion, indicating the role of
MAPKs in the induction of IL-6. The combination of either IL-17 plus
IL-1 or IL-17 plus TNF- enhanced IL-6 secretion and IL-6 mRNA
expression; in particular, the effects of IL-17 plus TNF- were much
stronger than those induced by IL-17 plus IL-1. TNF--induced IL-6
mRNA degraded rapidly at any concentrations, and the combination of
IL-17 and TNF- markedly enhanced IL-6 mRNA stability. This indicates
that the effects of IL-17 plus TNF- were regulated at the
post-transcriptional level. In conclusion, pancreatic periacinar
myofibroblasts secreted a large amount of IL-6 in response to
proinflammatory cytokines. These cells might play an important role in
the pathogenesis of acute pancreatitis via IL-6
secretion. |
Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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, IL-1, and IL-6) may
play a central role and mediate the systemic complications of the
disease (1, 2). The release of these proinflammatory
mediators is initially limited to the pancreas, but they subsequently
extend to various distant sources during the course of the disease
(1). IL-6 plays an important role in the development of the acute phase response in various tissues via its broad proinflammatory actions (3, 4). Evidence obtained in studies of experimental animals and supported by data in humans suggests that excessive production of IL-6 is involved in the pathogenesis of acute pancreatitis. For example, in experimental acute pancreatitis, IL-6 has been reported to be associated with distant organ complications (5), and the aggravation of experimental acute pancreatitis was observed in IL-6 transgenic mice (6). In patients with acute pancreatitis, systemic complications are associated with increased IL-6 secretion by isolated peripheral blood monocytes (7). In other studies, serum IL-6 level is a specific and sensitive marker of development of pulmonary failure, and peak IL-6 levels were increased in severe and lethal acute pancreatitis as well as in multiple organ failure (8, 9, 10, 11, 12).
We previously reported the isolation of human pancreatic periacinar
myofibroblasts, which are located in the periacinar region of the
normal human pancreas (13). These cells are characterized
by expression of type I, III, and IV collagen, fibronectin, prolyl
hydroxylase , laminin, vimentin, nonmuscle myosin, and -smooth
muscle actin (13). In addition, we have recently
demonstrated that these cells can secrete high amounts of IL-8,
monocyte chemoattractant protein
(MCP)3-1, and RANTES
in response to the monocyte/macrophage-derived cytokines, IL-1, and
TNF- (14). These cells are likely to be important not
only in the regulation of acinar cell functions such as digestive
enzyme secretion, but also in the induction of inflammatory responses
in the pancreas.
In this study, to further understand the extent to which periacinar
myofibroblasts participate in local and systemic inflammatory responses
in acute pancreatitis, we assessed the expression of IL-6 in these
cells. In particular, we focused on the role of IL-17, which is a newly
identified T cell-derived proinflammatory cytokine, and its secretion
is strictly limited in activated CD4+ and
CD8+ T lymphocytes (15, 16, 17, 18, 19, 20). The
secretion of a large amount of IL-6 by pancreatic periacinar
myofibroblasts suggests that these cells play a critical role in the
initiation and maintenance of the acute inflammatory process in the
pancreas. Furthermore, the regulation of IL-6 secretion in the pancreas
is dependent not only on the cytokines derived from
monocytes/macrophages (IL-1 and TNF-), but also on the T
cell-derived factor (IL-17).
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Recombinant human IL-1, IL-17, and TNF- were obtained from
R&D Systems (Minneapolis, MN). The inhibitor of p42/44
mitogen-activated protein kinases (MAPKs; PD98059 and U0216; Refs.
21, 22) and the inhibitor of p38 MAPK (SB203580; Ref.
23) were purchased from Cell Signaling Technology
(Beverly, MA). All other reagents used in this study were purchased
from Sigma-Aldrich (St. Louis, MO).
Cells
Normal human pancreatic tissue was obtained under informed
consent from patients who underwent total gastropancreatectomy due to
gastric cancer, and pancreatic periacinar myofibroblasts were isolated
using the method described by Saotome et al. (13). The
purity of the cells, determined by the expression of -smooth muscle
actin, was over 99%. Cells were cultured in DMEM (Nikkenkagaku, Kyoto,
Japan) containing 10% FBS (Life Technologies, Grand Island, NY). All
culture media were supplemented with 50 U/ml penicillin and 50 µg/ml
streptomycin. All experiments were performed using the cells of passage
number 3–6. The cells were seeded at a density of 2.5 x
105 cells/ml, and the cell culture media was
changed every third day. All experiments were performed after cells had
achieved confluence.
Quantification of human IL-6, IL-8, and MCP-1
The amounts of antigenic IL-6, IL-8, and MCP-1 in the samples were determined by sandwich ELISA kits purchased from BioSource International (Camarillo, CA).
Northern blot analysis
Total cellular RNA was isolated by the acid guanidinium thiocyanate-phenol-chloroform method (24). Northern blot was performed according to the method described previously (14). The hybridization was performed with 32P-labeled human IL-6 probe generated by a random primed DNA labeling kit (Amersham, Arlington Heights, IL) and evaluated by autoradiography. The human IL-6 cDNA probe was prepared from a monolayer of HUVECs by the reverse transcription-PCR method using primers: 5'-TGAGAAAGGAGACATGTAAC corresponding to nucleotides 262–282 isolated by May et al. (25), and 3'-AGTGTCCTAACGCTCATACT corresponding to nucleotides 824–803. The PCR products were ligated into the TA cloning vector (Promega, Madison, WI) and sequenced by the dideoxynucleotide chain termination method (26).
Nuclear extracts and EMSA
Nuclear extracts were prepared from cells exposed to IL-1,
IL-17, and TNF- for 1.5 h by the method of Dignam and Roeder
(27). Consensus oligonucleotides of NF-B
(5'-AGTTGAGGGGACTTTCCCAGCC; Ref. 28) were
used. The consensus sequence for binding of NF-B is underlined.
Oligonucleotides were 5' end-labeled with T4 polynucleotide kinase
(Promega) and [
-32P]ATP (Amersham). Binding
reactions were performed according to methods described previously
(14). Supershift experiments were performed as described
above except that 1 µl of Ab to each transcription factor was added
to the binding mixture in the absence of labeled probe. Antisera
specifically recognizing each transcriptional factor were purchased
from Santa Cruz Biotechnology (Santa Cruz, CA). Experiments with
unlabeled oligonucleotides used a 100-fold molar excess relative to the
radiolabeled oligonucleotide.
Western blot analysis
Cells were exposed to cytokines in the presence or absence of inhibitors for the indicated periods of time. Cells were then washed with PBS and lysed in SDS sample buffer containing 100 µM orthovanadate. Lysates were homogenized and protein content was determined by using the Bradford method. For Western blotting, 10 µg of protein from each sample was subjected to SDS-PAGE on a 4–20% gradient gel under reducing conditions. Proteins were then electrophoretically transferred onto a nitrocellulose membrane. The Abs against phosphorylated and total MAPKs were purchased from Cell Signaling Technology, and peroxidase-conjugated second Abs were purchased from Amersham. Subsequently, detection was performed using the ECL Western blotting system (Amersham).
Measurement of radioactivity
The radioactivity of each band of Northern blotting and EMSA was determined by the Instant Imager Electronic Autoradiography system (model no. 2024/417257; Packard Instruments, Meriden, CT). For comparison of radioactivity, each radioactivity was converted to relative radioactivity to the value of medium alone.
Statistical analysis
The data are expressed as means ± SD. The variance was analyzed by the Bartlett test (Statview for Macintosh, Version 4.5; Abacus Concepts, Berkeley, CA). Subsequently, statistical significance of changes was determined by the Fisher’s protected least significance difference test (Statview for Macintosh, Version 4.5). Differences resulting in p values <0.01 were considered significant.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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, and TNF-
Human pancreatic periacinar myofibroblasts were incubated for
24 h with increasing concentrations of IL-17, IL-1, or TNF-,
and secreted IL-6 levels in supernatants were determined by ELISA. As
shown in Fig. 1
, the addition of these
cytokines induced a dose-dependent increase in IL-6 secretion. The
effects of IL-17 were modest as compared with those induced by IL-1
or TNF-.
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, and TNF-
The kinetics of the effects of IL-17, IL-1, and TNF- on IL-6
mRNA expression were evaluated in pancreatic periacinar myofibroblasts
(Fig. 2). The cells were stimulated with
IL-17 (200 ng/ml), IL-1 (10 ng/ml), or TNF- (100 ng/ml), and IL-6
mRNA abundance was determined by Northern blotting. IL-17, IL-1, and
TNF- induced a rapid increase in the accumulation of IL-6 mRNA, and
these reached a maximum at 6 h after stimulation. Thereafter, the
induced IL-6 mRNA abundance decreased gradually. To detect the effects
of IL-17, the prolonged exposure of films was required in the process
of autoradiography.
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The expression of IL-6 genes is regulated by the activation of
specific transcription factors such as NF-B (29, 30).
To elucidate the mechanisms underlying the response to IL-17, IL-1,
and TNF-, we evaluated the activation of the transcription factors
NF-B in pancreatic periacinar myofibroblasts. As demonstrated in
Fig. 3A, stimulation with
either IL-17 (200 ng/ml), IL-1 (10 ng/ml), or TNF- (100 ng/ml)
for 1.5 h induced a increase in NF-B DNA-binding activity. The
effects of IL-17 were rather weak as compared with those induced by
IL-1 and TNF-. The specificity of this reaction was confirmed by
the addition of cold oligo-DNA, which abolished the reactive band. The
addition of Abs directed against a 50,000-Da subunit (p50) and a
65,000-Da subunit (p65) of NF-B induced supershifts of the binding
complexes, indicating that this binding complex was a heterodimer
consisting of p50 and p65 subunits.
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B activation, we assessed the actions of
NF-B inhibitors such as the pyrrolidine derivative of
dithiocarbamate (PDTC) (31) and
tosyl-phe-chloromethylketone (TPCK) (32) on IL-6 mRNA
expression. A role for oxygen radicals in mediating NF-B activation
has been postulated, and antioxidants such as PDTC have been shown to
block NF-B activation in several cell lines (31). As
demonstrated in Fig. 3
B, the addition of PDTC blocked
IL-17-, IL-1-, and TNF--induced IL-6 gene expression. TPCK blocks
NF-B activation by preventing the degradation of the predominant
inhibitory molecule, IB, and inhibits the translocation of
NF-B into the nucleus (32). TPCK potently abrogated
IL-17-, IL-1-, and TNF--induced IL-6 mRNA expression in
periacinar myofibroblasts. These findings indicate that the activation
of NF-B may play a major role in the induction of IL-6 mRNA
expression in these cells.
IL-17, IL-1, and TNF- induce the activation of MAPKs
In various cells, the MAPK family has been shown to play an
important role in regulating gene expression in response to
inflammatory mediators (33). However, it has not fully
been studied whether MAPKs participate in IL-17 signaling. To assess
whether similar responses are involved in our system, we evaluated the
effects of IL-17, IL-1, and TNF- on MAPK phosphorylation in
pancreatic periacinar myofibroblasts. As shown in Fig. 4A, IL-17, IL-1, and
TNF- induced a phosphorylation of p42/44 (extracellular regulated
kinase (ERK)) and p38 MAPKs as early as 5 min after the stimulation,
and these reached a maximum at 15 min. The effects of IL-17 were weaker
than those induced by IL-1 or TNF-. These results indicate that
MAPK pathways are rapidly activated by IL-17, IL-1, and TNF- in
pancreatic periacinar myofibroblasts.
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To evaluate the effects of MAPKs on the induction of IL-6
secretion by IL-17, IL-1, or TNF- in pancreatic periacinar
myofibroblasts, the effects of SB203580, PD98059, and U0216 were
examined. As shown in Fig. 4B, each inhibitor significantly
reduced IL-17-, IL-1-, and TNF--induced IL-6 secretion. The
inhibitory effects of SB203580 and U0216 were stronger than those
induced by PD98059.
Combination effects of IL-17 plus IL-1 and/or IL-17 plus
TNF-
The combined effects of either IL-17 plus TNF- or IL-17 plus
IL-1 were evaluated. The cells were incubated with stimulators for
24 h, and IL-6 levels were determined. As shown in Fig. 5, IL-17 dose-dependently enhanced
TNF-- or IL-1-induced IL-6 secretion. Although the effects of
IL-17 itself on IL-6 secretion were modest, the enhancing effects of
IL-17 on TNF-- or IL-1-induced IL-6 secretion were strong. The
enhancing effects of IL-17 on TNF--induced IL-6 secretion were much
stronger than those on IL-1-induced IL-6 secretion. When comparing
the effects of IL-17 on IL-6 secretion with those on IL-8 or MCP-1
secretion, the enhancing effects of IL-17 on TNF--induced IL-6
secretion were much stronger than those on IL-8 or MCP-1 secretion
(Fig. 6). In these cells, incubation with
IL-1 (1 ng/ml) and TNF- (10 ng/ml) for 24 h induced IL-8
secretion of 528 ± 45 ng/105 cells and
287 ± 23 ng/105 cells, respectively. The
stimulation with IL-1 (1 ng/ml) and TNF- (10 ng/ml) for 24 h
also induced MCP-1 secretion of 305 ± 31
ng/105 cells and 390 ± 39
ng/105 cells, respectively.
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or those of IL-17 plus
TNF- on IL-6 mRNA expression were investigated. Cells were
stimulated for 3 h, and then IL-6 mRNA abundance was determined by
Northern blotting. As shown in Fig. 7, these combinations increased IL-6 mRNA abundance as compared with the
effects of individual cytokines. The combination of IL-17 plus TNF-
exerted a stronger effect than that of IL-17 and IL-1. These
findings were compatible with the results at a protein level.
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on NF-B activation and IL-6
mRNA stability
To assess the molecular mechanisms involved in the combined
effects of IL-17 plus TNF-, NF-B activation was evaluated by
EMSAs. As shown in Fig. 8A,
the combination of IL-17 plus TNF-, as well as IL-17 plus IL-1,
exerted modest effects on NF-B DNA-binding activities, suggesting
that this transcriptional mechanism might not play a major role in the
combined effects of IL-17 plus TNF-.
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are
dependent on a result of increased mRNA stability, the cells were
stimulated with cytokines for 3 h, washed, and then treated with
actinomycin D (5 µg/ml) for various time periods to block further RNA
transcription (Fig. 8, B and C). In the cells
treated with TNF- (10 ng/ml) alone, IL-6 mRNA abundance rapidly
decreased and only 30% of IL-6 mRNA was remaining at 5 h after
the addition of actinomycin D. A similar response was induced by
high-dose TNF- (100 ng/ml; data not shown). The combination of IL-17
(200 ng/ml) plus TNF- (10 ng/ml) markedly prolonged the rate of IL-6
mRNA degradation; 86% of IL-6 mRNA was remaining after 5 h. IL-17
also induced a stabilization of IL-6 mRNA induced by high-dose TNF-
(100 ng/ml; data not shown). Thus, the combined effects of IL-17 and
TNF- on IL-6 mRNA abundance are associated with the increasing
actions on IL-6 mRNA stabilities.
In contrast, IL-6 mRNA induced by high-dose IL-1 (10 ng/ml) was
stable for 5 h, whereas IL-6 mRNA induced by low-dose IL-1 (0.1
ng/ml) decreased rapidly (Fig. 8B). In contrast to the
effects on TNF--induced IL-6 mRNA, IL-17 did not affect the
stability of IL-1 (0.1 ng/ml)-induced IL-6 mRNA (Fig. 8, B and C).
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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2 µg per 105 cells per 24
h) in response to monocyte/macrophage-derived cytokines (IL-1 and
TNF-) and a factor derived from activated T cells (IL-17). IL-6
secretion in pancreatic myofibroblasts is much stronger than that
reported in other cell types (34, 35, 36). It is likely that
pancreatic periacinar myofibroblasts may play a pivotal role in the
pathophysiology of acute pancreatitis and in the development of
systemic complications via IL- 6 secretion.
IL-17 is a newly identified T cell-specific cytokine. Human IL-17 is an
20-kDa glycoprotein of 155 amino acids, the sequence of which
exhibits close homology to both CTLA Ag-8 and the open reading frame 13
of T lymphotropic Herpesvirus saimiri (15, 16).
IL-17 secretion is strictly limited to activated
CD4+ and CD8+ T lymphocytes
and is predominantly secreted by the memory
CD45RO+ cells (17, 18, 19). Both the Th1
and Th2 subsets of CD4+ cells release IL-17. In
contrast, IL-17R is widely distributed on various cell types (20, 37), and there is increasing evidence that IL-17 is a mediator
of inflammatory responses in various tissues (34, 35, 38, 39, 40, 41). Thus, IL-6 induction by IL-17 in pancreatic periacinar
myofibroblasts suggests a role for T cells in the pathogenesis of acute
pancreatitis. Although the role of T cells in the pathogenesis of acute
pancreatitis has not been fully investigated, recent clinical and
experimental studies have demonstrated that T cells affect inflammatory
responses involved in the pathophysiology of acute pancreatitis
(42, 43, 44).
Previously, only one report has demonstrated the combined effects of
IL-17 plus IL-1 on IL-6 secretion in synoviocytes (35).
In pancreatic periacinar myofibroblasts, the combination of IL-17 with
either IL-1 or TNF- strongly enhanced IL-6 secretion. These
responses were clearly observed even at low concentrations. For
example, the combination of IL-17 (10 ng/ml) plus IL-1 (0.01 ng/ml)
and/or IL-17 (10 ng/ml) plus TNF- (0.1 ng/ml) induced a large amount
of IL-6 secretion. These responses were also confirmed at the mRNA
level. The combined effects on IL-6 secretion were much stronger with
the combination of IL-17 plus TNF- than with the combination of
IL-17 plus IL-1. Furthermore, this strong effect of IL-17 plus
TNF- was specific for IL-6 secretion. These results indicate that
cytokines produced by monocytes/macrophages (IL-1 and TNF-) and
activated T cells (IL-17) can cooperate in the induction of IL-6
secretion in pancreatic periacinar myofibroblasts at the low levels
that can be easily achieved in vivo.
Many cytokine-inducible responses are mediated by one of the important
DNA-binding proteins, such as NF-B (28). The promoter
regions of the human IL-6 genes have been cloned and are shown to
contain putative consensus binding motifs for NF-B (29, 30). Our results demonstrated that the activation of NF-B was
necessary for not only IL-1- and TNF--induced IL-6 gene
expression, but was also induced by IL-17 in pancreatic periacinar
myofibroblasts. The evidence supporting this conclusion may be
summarized as follows: 1) IL-17 rapidly induced nuclear proteins that
exhibited binding to an oligonucleotide containing an NF-B consensus
recognition motif. Binding specificity was confirmed by experiments in
which the binding was blocked by the addition of excess cold-NF-B
oligonucleotide. 2) The inhibition of NF-B activation by PDTC and
TPCK caused a marked decrease in IL-17-induced IL-6 mRNA expression.
PDTC and TPCK are potent inhibitors of NF-B activation (31, 32). It is likely that the effects of IL-17 on IL-6 secretion
may be mainly regulated at the transcriptional levels via NF-B
activation in pancreatic periacinar myofibroblasts.
MAPK activation has been regarded as another important signaling event
in response to proinflammatory stimuli. Three subgroups of the MAPK
family have been identified, and all are phosphorylated on tyrosine and
threonine residues by upstream kinases, the MAPK kinases (MEKs). The
p44 and p42 ERK1 and ERK2 mediate responses mainly to mitogenic
stimuli, and the Jun NH2-terminal kinases and p38
mediate responses to cellular stress (45, 46, 47, 48). In
this study, we show that IL-17, as well as IL-1 and TNF-,
activate the two groups of MAPKs in pancreatic periacinar
myofibroblasts. Similar to the responses induced by IL-1 and
TNF-, the MAPK activation by IL-17 was maximal after 15 min and then
declined. Like the effects on NF-B activation, the effects of IL-17
on MAPK activation were weaker than those induced by IL-1 or
TNF-. The role of MAPKs in IL-17-, IL-1-, and TNF--induced
IL-6 secretion was investigated in pancreatic periacinar myofibroblasts
by using specific inhibitors. The imidazole compound SB203580 is a
specific inhibitor of p38 MAPK (23). SB203580 caused a
significant decrease in IL-17-, IL-1-, and TNF--induced IL-6
secretion, indicating that p38 activation is involved in IL-17,
IL-1-, and TNF--induced IL-6 secretion. This observation is
compatible with the recent report by Craig et al. (49)
indicating that the stimulation of p38 MAPK by the MEK, MKK6, activates
NF-B DNA-binding activity and induces IL-6 secretion. In contrast,
the role of ERK1/2 MAPKs in IL-6 induction has not fully been
investigated (50). In this study, we addressed the role of
ERK1/2 in our system. PD098059 is a specific inhibitor of MEK1
(21), the kinase directly upstream to ERK1/2, and U0216 is
a specific inhibitor of MEK1 and MEK2 (22), respectively.
U0216 more potently blocked the phosphorylation of ERK1/2 as compared
with PD098059. PD098059 and U0216 caused a significant inhibition on
IL-17-, IL-1-, and TNF--induced IL-6 secretion. Thus, we
concluded that ERK1/2 MAPKs also participate in IL-6 secretion by
IL-17, IL-1, and TNF- in pancreatic periacinar
myofibroblasts.
The molecular mechanism involved in the strong induction of IL-6
secretion by IL-17 plus TNF- remains to be clarified. These
cytokines initiate signaling cascades leading to NF-B activation via
distinct cell surface receptors that use the TNFR-associated factor
(TRAF) family of adaptor proteins as signal transducers. TNF-
requires TRAF2 activation to induce subsequent molecular events,
whereas IL-17, as well as IL-1, uses TRAF6 (51, 52).
So, the possibility that the combination of IL-17 plus
TNF--modulated NF-B DNA-binding activity was initially proposed.
However, the combination of either IL-17 and TNF- or IL-17 plus
IL-1 induced a modest increase in NF-B DNA-binding activities,
indicating that the NF-B-mediated transcriptional mechanism did not
play a major role. In contrast, the combination of IL-17 plus TNF-
markedly enhanced IL-6 mRNA stabilities. These effects were not induced
by the combination of IL-17 plus IL-1. Thus, these observations
highly suggested that the strong induction of IL-6 secretion by IL-17
plus TNF- might be closely associated with the post-transcriptional
mechanisms that enhance IL-6 mRNA stabilities. The precise mechanisms
involved in the enhancement of IL-6 mRNA stabilities should be
clarified in the future.
In conclusion, one of the sources of IL-6 secretion in human pancreas
was identified. T cell-derived IL-17 and monocyte/macrophage-derived
IL-1 and TNF- induced IL-6 secretion in human pancreatic
periacinar myofibroblasts. These findings may explain the linkage
between monocytes/macrophages- and T cell-mediated immune responses in
the pathophysiology of acute pancreatitis. These observations reinforce
the concept that T cells can collaborate with monocytes/macrophages in
the promotion and shaping of inflammatory responses in the
pancreas.
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Footnotes |
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2 Address correspondence and reprint requests to Dr. Akira Andoh, Department of Internal Medicine, Shiga University of Medical Science, Seta Tukinowa, Otsu 520-2192, Japan. E-mail address: andoh{at}belle.shiga-med.ac.jp
3 Abbreviations used in this paper: MCP, monocyte chemoattractant protein; MAPK, mitogen-activated protein kinase; PDTC, pyrrolidine derivative of dithiocarbamate; TPCK, tosyl-phe-chloromethylketone; ERK, extracellular regulated kinase; MEK, MAPK kinase; TRAF, TNFR-associated factor.
Received for publication August 16, 2001. Accepted for publication November 2, 2001.
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F. Shen, Z. Hu, J. Goswami, and S. L. Gaffen Identification of Common Transcriptional Regulatory Elements in Interleukin-17 Target Genes J. Biol. Chem., August 25, 2006; 281(34): 24138 - 24148. [Abstract] [Full Text] [PDF]
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 H. Aoki, H. Ohnishi, K. Hama, T. Ishijima, Y. Satoh, K. Hanatsuka, A. Ohashi, S. Wada, T. Miyata, H. Kita, et al. Autocrine loop between TGF-beta1 and IL-1beta through Smad3- and ERK-dependent pathways in rat pancreatic stellate cells Am J Physiol Cell Physiol, April 1, 2006; 290(4): C1100 - C1108. [Abstract] [Full Text] [PDF]
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 A. van den Berg, M. Kuiper, M. Snoek, W. Timens, D. S. Postma, H. M. Jansen, and R. Lutter Interleukin-17 Induces Hyperresponsive Interleukin-8 and Interleukin-6 Production to Tumor Necrosis Factor-{alpha} in Structural Lung Cells Am. J. Respir. Cell Mol. Biol., July 1, 2005; 33(1): 97 - 104. [Abstract] [Full Text] [PDF]
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 S. de Haij, A. C. Bakker, R. N. van der Geest, G. Haegeman, W. Vanden Berghe, J. Aarbiou, M. R. Daha, and C. van Kooten NF-{kappa}B Mediated IL-6 Production by Renal Epithelial Cells Is Regulated by C-Jun NH2-Terminal Kinase J. Am. Soc. Nephrol., June 1, 2005; 16(6): 1603 - 1611. [Abstract] [Full Text] [PDF]
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S. Yamazaki, T. Muta, S. Matsuo, and K. Takeshige Stimulus-specific Induction of a Novel Nuclear Factor-{kappa}B Regulator, I{kappa}B-{zeta}, via Toll/Interleukin-1 Receptor Is Mediated by mRNA Stabilization J. Biol. Chem., January 14, 2005; 280(2): 1678 - 1687. [Abstract] [Full Text] [PDF]
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M. J. Ruddy, F. Shen, J. B. Smith, A. Sharma, and S. L. Gaffen Interleukin-17 regulates expression of the CXC chemokine LIX/CXCL5 in osteoblasts: implications for inflammation and neutrophil recruitment J. Leukoc. Biol., July 1, 2004; 76(1): 135 - 144. [Abstract] [Full Text] [PDF]
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M. J. Ruddy, G. C. Wong, X. K. Liu, H. Yamamoto, S. Kasayama, K. L. Kirkwood, and S. L. Gaffen Functional Cooperation between Interleukin-17 and Tumor Necrosis Factor-{alpha} Is Mediated by CCAAT/Enhancer-binding Protein Family Members J. Biol. Chem., January 23, 2004; 279(4): 2559 - 2567. [Abstract] [Full Text] [PDF]
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S. Bamba, A. Andoh, H. Yasui, J. Makino, S. Kim, and Y. Fujiyama Regulation of IL-11 expression in intestinal myofibroblasts: role of c-Jun AP-1- and MAPK-dependent pathways Am J Physiol Gastrointest Liver Physiol, August 8, 2003; 285(3): G529 - G538. [Abstract] [Full Text] [PDF]
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S. de Haij, I. M. Adcock, A. C. Bakker, S. J. P. Gobin, M. R. Daha, and C. van Kooten Steroid Responsiveness of Renal Epithelial Cells. DISSOCIATION OF TRANSREPRESSION AND TRANSACTIVATION J. Biol. Chem., February 7, 2003; 278(7): 5091 - 5098. [Abstract] [Full Text] [PDF]
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S Fujino, A Andoh, S Bamba, A Ogawa, K Hata, Y Araki, T Bamba, and Y Fujiyama Increased expression of interleukin 17 in inflammatory bowel disease Gut, January 1, 2003; 52(1): 65 - 70. [Abstract] [Full Text] [PDF]
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J. Maertzdorf, A. D. M. E. Osterhaus, and G. M. G. M. Verjans IL-17 Expression in Human Herpetic Stromal Keratitis: Modulatory Effects on Chemokine Production by Corneal Fibroblasts J. Immunol., November 15, 2002; 169(10): 5897 - 5903. [Abstract] [Full Text] [PDF]
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A. Andoh, S. Fujino, S. Bamba, Y. Araki, T. Okuno, T. Bamba, and Y. Fujiyama IL-17 Selectively Down-Regulates TNF-{alpha}-Induced RANTES Gene Expression in Human Colonic Subepithelial Myofibroblasts J. Immunol., August 15, 2002; 169(4): 1683 - 1687. [Abstract] [Full Text] [PDF]
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