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,
Departments of
*
Molecular Oncology,
Molecular Biology,
Pathology, and
Immunology, Genentech, Inc., South San Francisco, CA 94080
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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in several tissues and elevated serum
TNF-
were also noted. In addition, IL-17E induces G-CSF production
in vitro and mIL-17E-transgenic mice had increased serum G-CSF and
exhibit neutrophilia, a property shared by IL-17. Moreover, exposure to
mIL-17E elicited pathological changes in multiple tissues, particularly
liver, heart, and lungs, characterized by mixed inflammatory cell
infiltration, epithelial hyperplasia, and hypertrophy. Taken together,
these findings suggest that IL-17E is a unique pleiotropic cytokine and
may be an important mediator of inflammatory and immune
responses. |
Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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The identification of IL-17Rh1 (also called IL-17ER, Evi27
or IL-17BR) as a receptor for IL-17E (5) and the
observation that other IL-17R-like molecules are encoded in the human
genome (our unpublished observations) suggest that members of the IL-17
family have a unique cognate receptor(s) and may therefore possess
distinct biological functions. Interestingly, the murine ortholog of
IL-17Rh1 was identified at Evi27, a common site of retroviral
integration in BXH2 murine leukemias. The proviral integrations result
in increased expression of the receptor, and its role in myeloid
leukemia and growth and/or differentiation of hemopoietic cells has
also been suggested (16). IL-17B has also been identified
as a putative ligand for IL-17Rh1, although the apparent weaker binding
suggests that it may use another, as yet unidentified, receptor
(4). IL-17Rh1 transcripts are expressed in several adult
tissues. In humans, abundant levels of IL-17Rh1 mRNA were detected in
kidneys and liver, with lower abundance in testes, brain, small
intestine, and other tissues. Similar expression patterns were observed
in the mouse (5). Similar to IL-17, IL-17E was found
capable of activation of NF-
B and stimulation of production of the
proinflammatory chemokine IL-8 in cell cultures (5).
Here, we have developed a transgenic mouse model overexpressing murine (m)3 IL-17E (mIL-17E) under the control of the muscle myosin L chain 2 gene promoter. We found that systemic overexpression of mIL-17E up-regulates gene expression of Th2 cytokines, including IL-4, IL-10, and IL-13 in many tissues. Serum levels of IL-13 and IL-5 as well as circulating IgE and IgG1 are increased in transgenic mice. Furthermore, these profound immunological changes in mIL-17E-transgenic (TG) mice are associated with pathological changes in multiple tissues, characterized by a mixed immune infiltration and epithelial cell hyperplasia.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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All animal protocols were approved by an institutional use and care committee. The cDNA encoding for the mature mIL-17E protein with the putative signal sequence from human IL-17E was cloned into a plasmid containing rat myosin L chain promoter sequence (17, 18), followed by a sequence derived from the human growth hormone gene including the fourth and fifth exons and 3' untranslated region plus poly(A) to improve the expression of the transgene. The expression cassette fragment was excised, purified, and injected into one-cell mouse eggs prepared from FVB x FVB matings. Genotyping was performed by PCR analysis of the DNA from tail biopsies using primers against specific sequences in the expression cassette. Expression levels of mIL-17E were determined by Taqman RT-PCR (PerkinElmer, Norwalk, CT) on total RNA samples derived from muscle biopsy.
Determination of gene expression
Total RNA samples from various mouse tissues were prepared using
TRIzol reagent according to the manufacturer’s instruction (Life
Technologies, Grand Island, NY). The mRNA expression levels for various
murine cytokines, chemokines, adhesion molecules, and IL-17Rh1 (IL-17E
receptor) were determined by Taqman RT-PCR (PerkinElmer) using
gene-specific primers and probes as follows. For mIL-6: primers, 5'-AAG
GAG TGG CTA AGG ACC AA-3' and 5'-GTT TGC CGA GTA GAT CTC AAA G-3'; and
probe, FAM ACC ATC CAA TTC ATC TTG AAA TCA CTT GAA G TAMARA. For
mIL-10: primers, 5'-GAC TGG CAT GAG GAT CAG CA and 5'-CCG CAG CTC TAG
GAG CAT GT; and probe, FAM CAC TTC CCA GTC GGC CAG AGC C TAMARA. For
mIL-13: 5'-AGC CTG TGG CCT GGT CC and 5'-TCA AGA AGA AAT GTG CTC AAG
CTG; and probe, FAM CAC AGG GCA ACT GAG GCA GGC A TAMARA. For mG-CSF:
primers, 5'-CCT GCA GGC TCT ATC GGG TA and 5'-GCA ACA TCC AGC TGA AGC
AA; and probe, FAM CCT GCC CTG GCC CCC ACC T TAMARA. For mIL-4: 5'-GAG
CTG CAG AGA CTC TTT CG and 5'-ACT CAT TCA TGG TGC AGC TTA; and probe,
FAM GCT TTT CGA TGC CTG GAT TCA TCG TAMARA. For mIL-9: 5'-AAA GGA TAG
TTG AAG TCC TAA AGA ACA and 5'-TCT GGT TGC ATG GCT TTT C; and probe,
FAM CAC GTG TCC GTC CTT TTC CTG C TAMARA. For mTNF-: 5'-TGG GAC AGT
GAC CTG GAC TGT and 5'-GGC TCC AGT GAA TTC GGA AAG; and probe, FAM CAC
CAC CAT CAA GGA CTC AAA TGG GC TAMARA. For mIFN-: primers, 5'-AGC
TCA TCC GAG TGG TCC AC and 5'-AAA ATT CAA ATA GTG CTG GCA GAA; and
probe, FAM AGC TGT TGC CGG AAT CCA GCC TC TAMARA. For mIL-5: primers,
5'-GTG CCT GGA GCA GCT GGA T and 5'-GTG GCT GGC TCT CAT TCA CA; and
probe, FAM TTG GAA AAG AAA AGG GAC ATC TCC TTG CA TAMARA. For mGRO:
primers, 5'-TGCACCCAAACCGAAGTCA and 5'-AGCTTCAGGGTCAAGGCAAG; and probe,
FAM AGCCACACTCAAGAATGGTCGCGAG TAMARA. For mICAM-1: primers,
5'-CCTAAGATGACCTGCAGACGG and 5'-TTTGACAGACTTCACCACCCC; and probe,
FAM CAGATGGTGCCCTGCTGCCCA TAMARA. For mVCAM-1: primers,
5'-CCCTGAATACAAAACGATCGC and 5'-CAGCCCGTAGTGCTGCAAG; and probe, FAM
CAAATCGGTGACTCCATGGCCCTC TAMARA. For mouse monocyte chemoattractant
protein-1: primers, 5'- GATCGCCAAGGAGCTCAACT and
5'-TGGCGTCGATTACAGAACCA; and probe, FAM CGACCGGGAGGTGGTGAGGGT
TAMARA. For mIL-17ER: primers, 5'-GCT GGA TAC TCC GGG GGC CA and 5'-
TGC CACTCA CGC AGA TCT TG; and probe: FAM CAG CAT CCG CTT GTT GAA GGC
CA TAMARA. Expression levels of 18S rRNA were used as normalization
control.
Histological analysis
Routine necropsy was performed. Tissues for light microscopy were collected and fixed overnight in 10% neutral buffered Formalin, embedded in paraffin, sectioned at 5 µm, and stained with H&E.
FACS analysis
Blood samples were collected and processed, and FACS analyses were performed on EPICS XL-MCL (Coulter, Miami, FL) using various Abs (BD PharMingen, San Diego, CA) according to the manufacturers’ instructions.
Measurement of serum proteins
Serum IgG1 and IgG2a levels were assessed using a sandwich
ELISA. Anti-mouse IgG1- and IgG2a-coating Abs (BD PharMingen) were
diluted to 1.0 and 2.5 µg/ml in PBS (pH 7.2), respectively, and added
to separate 96-well plates (Nunc Immuno Plate Maxisorp; Nunc,
Naperville, IL), then incubated overnight at 4°C. Plates were washed
three times (0.05% Tween 20), blocked (0.5% BSA in PBS), and
incubated for 2 h at room temperature with gentle agitation, then
washed three times. Mouse IgG1 standard (10 µg/ml standard stock, lot
31357-30A) was diluted to 25 ng/ml in assay buffer (0.5% BSA and
0.05% Tween 20 in PBS), and 2-fold serial dilutions were performed to
create a seven-point standard curve ranging from 25 to 0.39 ng/ml.
Mouse IgG2a standard (Southern Biotechnology Associates, Birmingham,
AL) was diluted to 400 ng/ml in assay buffer, and 2-fold serial
dilutions were performed to create a seven-point standard curve ranging
from 400 to 6.25 ng/ml. Serum samples were serially diluted 2-fold in
assay buffer to fall within the respective standard curve ranges.
Standard or sample was added to each plate and incubated for 2 h
at room temperature with gentle agitation, then washed six times.
Biotinylated anti-mouse IgG1 and IgG2a detection Abs (BD
PharMingen) were diluted 1/2000 in assay buffer and added to each plate
at 100 µl/well, then incubated at room temperature for 1 h with
gentle agitation and then washed six times. Strepavidin-HRP (Amersham
Pharmacia Biotech, Piscataway, NJ) diluted 1/20,000 in assay buffer was
added and incubated for 30 min at room temperature with gentle
agitation, then washed six times. Tetramethylbenzidine substrate
solution (Kirkegaard & Perry, Gaithersburg, MD) was added to each well,
and color was allowed to develop for 4–6 min. The reaction was stopped
with 1 M phosphoric acid, and absorbance was read at 450 nm. Serum IgE
levels were assessed by sandwich ELISA using a mouse IgE OptEIA kit (BD
PharMingen). Serum IL-5, IL-13, G-CSF, IFN-, and TNF- were
measured using ELISA kits (R&D Systems, Minneapolis, MN) according to
the manufacturer’s instructions.
Recombinant proteins and cell cultures
NIH-3T3 and ST2 cells were grown in high glucose DMEM with 10% heat-inactivated FBS, 2 mM L-glutamine, 1x penicillin, and streptomycin. The cultures were initiated at 500,000 per 60-mm culture disk. All cultures were grown in triplicate. At 24 h, factors were added to the cultures; 4 and 24 h later, conditioned media were removed and frozen for ELISA, and cells were lysed for RNA extraction in the dish using an RNeasy kit according to the manufacturer’s instructions (Qiagen, Valencia, CA). The rIL-17 was purchased from R&D Systems. IL-17E was prepared as previously described (5).
Statistical analysis
For body weights, hematological analysis, and FACS of PBMC, statistical significance was determined by Student’s t test. Gene expression data were statistically analyzed by ANOVA using StatView software (Calabasas, CA). A value of p < 0.05 was taken as significant.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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The murine ortholog of IL-17E was identified through sequence
comparison with expressed sequence tag information (accession no.
AI430337) present in GenBank. Several cDNA clones were subsequently
isolated, and the longest cDNA clone encoded a partial signal sequence
and the predicted mature protein of murine IL-17E, which was 85%
identical to human IL-17E and 17–22% identical to other members of
the IL-17 family (Fig. 1
A).
Attempts including 5' racing, failed to identify cDNA that
contained an initiation codon. Analysis of mRNA expression in several
mouse tissues indicated that mIL-17E is expressed in brain, heart, and
testes. Little expression was detected in liver, lung, or spleen (Fig. 1B).
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TG mice have not been previously reported for any member of the
IL-17 family. Attempts to generate transgenic mice that ubiquitously
overexpress mIL-17 were unsuccessful (9). The reason for
this failure remains unknown, but it is probable that overexpression of
potent proinflammatory cytokine, such as IL-17 during early development
may be lethal. Thus, rat skeletal myosin L chain 2 promoter was chosen
to overexpress mIL-17E in TG mice (17, 18), as this
promoter is known to direct a high level gene expression starting 6–9
days after birth, presumably giving rise to circulating mIL-17E. The
mice were housed in a specific pathogen-free environment, and multiple
founders were analyzed. All TG pups were significantly smaller than
their non-TG littermates by 1 wk of age. This difference in body
weights was retained at 3, 4, 6, 12, and 13 wk of age (Fig. 1
C and data not shown), suggesting that the TG mice were
growth retarded. At 6 wk of age, most of the TG founder mice were
jaundiced (Fig. 1D), indicating bilirubin deposition in the
tissues. Consistent with this, serum levels of bilirubin were
significantly elevated in the mIL-17E-TG mice (1.78 mg/dl (TG) vs 0.05
mg/dl (non-TG); p = 0.008). In addition, serum levels
of liver enzymes were markedly elevated, including alkaline phosphatase
(886.7 U/L (TG) vs 223 U/L (non-TG); p = 0.018),
alanine aminotransferase (252 U/L (TG) vs 45 U/L (non-TG),
p = 0.008), and amylase (21414 U/L (TG) vs 3606 U/L
(non-TG); p = 0.015), suggestive of liver damage in the
mIL-17E-TG mice.
Overexpression of mIL-17E in TG mice induces gene expression of cytokines in multiple tissues
To understand the in vivo consequences of the overexpressed
mIL-17E, we first examined the gene profiles of both Th1 and Th2
cytokines. mIL-17E receptor, mIL-17ER, is expressed in multiple
tissues, especially abundant in liver and kidneys (4, 5).
Thus, we measured expression of inflammatory cytokines in these tissues
using quantitative RT-PCR assays. The transcripts for Th2 cytokines
IL-4 and IL-10 were significantly induced in liver, and IL-4, IL-10,
and IL-13 in kidneys from TG mice (Fig. 2, A and B).
Interestingly, we found that some of these cytokines were also
dramatically induced in lungs (IL-4 and IL-10; Fig. 2C),
heart (IL-10 and IL-13; data not shown), spleen (IL-4, IL-6, and IL-13;
data not shown), and intestines (IL-4, IL-5, IL-9, and IL-10; data not
shown) where normally a very low abundance of mIL-17ER was detected
(4, 5), suggesting that these tissues were also responsive
to IL-17E. We thus measured the mIL-17ER expression in these tissues in
TG mice. Remarkably, mIL-17ER mRNA was substantially increased in
multiple tissues, especially heart and lung (increased by 64- and
16-fold, respectively; Fig. 2D) and consistent with the idea
that IL-17E may enhance its signaling in peripheral tissues by
up-regulation of its own receptor. These cytokine profiles suggest that
IL-17E may drive a Th2-like response. However, when the gene expression
levels of Th1 cytokines were measured (e.g., IFN- and TNF-), we
also observed elevated levels of these messages in several tissues
(Fig. 2A and data not shown). Thus, the inflammatory
response induced by mIL-17E may not be strictly Th2 in character.
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To determine whether the elevated gene expression described above
gave rise to circulating cytokines and further affected Ab generation,
we measured serum levels of several cytokines and Abs using specific
ELISAs. Both Th2 cytokines, IL-13 and IL-5, were increased in
mIL-17E-TG mice (Fig. 3A).
However, serum TNF- was also induced in TG mice (Fig. 3A). Induction of serum IFN- was not detected (data not
shown) despite increased IFN- mRNA in some tissues (Fig. 2). In
addition, both serum IgE and IgG1 (characteristic of the Th2 response)
were significantly elevated in the TG mice, but serum levels of IgG2a
(Th1 in character) were not altered (Fig. 3B). Along with
the increased circulating eosinophils (see below), these findings
suggest that IL-17E induces a systemic Th2-biased response.
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In vivo expression of IL-17 via adenoviral-mediated delivery
causes neutrophilia in mice (9), but no effect on
eosinophils has been reported. To understand whether overexpression of
mIL-17E had a similar effect, FACS analyses of PBMC were performed
using specific cell surface markers. CD3+ T cells
or CD19+ B cells were significantly reduced in TG
mice compared with those of non-TG mice (Fig. 4A). However, there was no
change in the CD4+:CD8+
ratio (data not shown). When PBMC were stained for
GR-1+ neutrophils, we found that TG mice had
significantly increased circulating neutrophils (Fig. 4B).
Consistent with these findings, the absolute cell counts of neutrophils
were increased by 8- to 10-fold in TG mice. Interestingly, the absolute
counts of eosinophils were also dramatically increased (Fig. 4C), but the absolute number of lymphocytes was only
slightly reduced (Fig. 4C). FACS analyses of cells isolated
from spleen and lymph nodes also showed significantly increased
neutrophils in the TG mice (data not shown). When lymphocytes from
spleen and lymph nodes were examined, we found that
CD3+ T cells were reduced by 20% (only
significant in male TG mice; p = 0.009). In contrast,
CD19+ B cells appeared to be increased in the TG
mice, but this was not statistically significant (data not shown).
Additional experiments are needed to examine the direct impact of
IL-17E on the lymphocyte population. These findings suggest that IL-17E
stimulates hemopoiesis and causes neutrophilia and eosinophilia in
vivo. Although the underlying molecular mechanism remains to be further
elucidated, these effects may be mediated in part by increased IL-5 and
G-CSF (Figs. 2 and 3 and see below).
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and adhesion molecules
Like IL-17, IL-17E stimulates IL-8 production in cell cultures
(1, 5). To determine the effect of mIL-17E on the gene
expression of other chemokines and adhesion molecules in vivo that
might contribute to the immune infiltrate in tissues (see blow), we
examined mRNA levels for GRO, monocyte chemoattractant protein-1,
ICAM-1, and VCAM-1 in multiple tissues from the TG mice. The GRO
mRNA was significantly induced in liver, kidneys, lungs, and heart,
while ICAM-1 was increased in liver and VCAM-1 in kidneys (Fig. 2, A and B, and data not shown). These findings that
mIL-17E may induce production of chemokines and adhesion molecules in
epithelial cells, endothelial cells, and fibroblasts in various
tissues, contributing to the recruitment of neutrophils, lymphocytes,
and other infiltrating cells.
IL-17E stimulates G-CSF production
IL-17 stimulates the production of G-CSF, a potent inducer of
granulopoiesis, in vivo and from stromal cells in vitro (7, 9, 19). To determine whether G-CSF was induced by IL-17E in vivo,
its mRNA levels in TG tissues were measured. G-CSF mRNA levels were
markedly increased in liver, kidneys, and spleen (Fig. 2, A
and B, and data not shown). Consistent with this, serum
G-CSF was also dramatically induced in TG mice (Fig. 5A). IL-17 directly stimulates
G-CSF production from stromal cells, NIH-3T3, and ST2 (7).
To determine whether IL-17E has a similar activity, NIH-3T3 and ST2
were treated with rIL-17E. Like IL-17, IL-17E stimulated G-CSF mRNA
(Fig. 5, B and C). G-CSF protein production from
NIH-3T3 cells was confirmed by ELISA (Fig. 5D). These
findings suggest that IL-17E induces G-CSF production, and the
increased G-CSF may contribute to the granulopoiesis seen in
mIL-17E-TG mice.
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A comprehensive histological tissue survey showed that mIL-17E-TG
mice had chronic inflammation in multiple tissues. Tissues consistently
affected include liver, heart, lungs, lymph node, kidneys (renal pelvis
and mild glomerular changes), spleen, and urinary bladder. Inflammation
in these tissues was comprised of mixed infiltrates of neutrophils,
eosinophils, lymphocytes, plasma cells, and macrophages. In the liver,
all mIL-17E-TG mice evaluated had severe cholangiohepatitis with
adenomatous hyperplasia of bile ducts, periportal fibrosis, and
variable oval cell hyperplasia (Fig. 6, B vs A). Special stains, including Warthin Starry
and periodic acid-Schiff, were negative for Helicobacter
sp. and fungal elements, respectively (data not shown). In
the lungs, mIL-17E-TG mice consistently develop diffuse interstitial
and peribronchial inflammation, with more severe changes in the highest
expressing founders (Fig. 6, C and D). In
addition to the mixed inflammatory cell infiltrate described above,
alveolar spaces were filled with numerous macrophages that were
occasionally multinucleated and often distended with long, thin,
cytoplasmic crystals, similar to those reported in the lungs of other
mutant mouse models that have eosinophilic inflammation (20, 21). Consistent with these studies, crystals seen in the mIL-17E
TGs were stained with eosin, but not periodic acid-Schiff or Congo Red.
All IL-17E-TG mice examined had splenomegaly (data not shown). Splenic
weights showed that, on the average, the mIL-17E-TG spleen weighed up
to four times more than that of the non-TG littermates. Histologically,
the splenomegaly was attributable to extensive extramedullary
hemopoiesis (data not shown). Lymph nodes were also enlarged in the
IL-17E TGs due to expansion of medullary and cortical sinuses by
numerous plasma cells (data not shown). Thymic weights were slightly
reduced (data not shown). These histological findings suggest that
ubiquitous expression of mIL-17E causes profound pathological and
immunological changes in multiple organs.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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The biological consequences of IL-17E exposure have both interesting
similarities and clear distinctions to those reported for IL-17. Like
IL-17, IL-17E impacts diverse tissues. This reflects in part the broad
expression of its receptor (4, 5, 22). IL-17E promotes
substantial neutrophilia, a response that may be due to the observed
induction of G-CSF. IL-17 has also been shown to induce the production
of G-CSF and promote neutrophilia (6, 7, 9, 19).
Similarly, both IL-17 and IL-17E induce the local production of
chemokines that target neutrophils such as GRO and IL-8 (5, 8). Furthermore, both IL-17 and IL-17E are associated with
increased expression of ICAM-1 and other inflammatory cytokines
(1, 17). Although we could not exclude the possibility
that some of the actions elicited by IL-17E might be mediated by IL-17,
serum IL-17 was not elevated in IL-17E-TG mice (data not shown).
Additional experiments using Abs against IL-17 or cells or mice
deficient in IL-17/IL-17R are required to address these issues. In
contrast, IL-17E overexpression resulted in the promotion of a systemic
Th2-biased immune response. This response has not been noted with
chronic IL-17 exposure (9). It should be mentioned that
IL-17 can be produced by both Th1 and Th2 subsets, and it has not been
strongly associated with either the Th1 or Th2 response (23, 24). The Th2 feature of this response in the TG mice was
characterized by cytokine profile, the presence of increased serum IgE
and IgG1, and an increase in eosinophil number. It was noted that in
vivo expression of IL-17 increased the peripheral white blood cell
count and 2-fold increases in lymphocytes (6, 9). In
contrast, mIL-17E-TG mice appeared to be slightly lymphopenic. Further
studies are required to understand the effect of IL-17E on
lymphopoiesis and subtypes of lymphocytes. These comparisons should be
viewed with caution, since the phenotype of IL-17-TG mice has not been
reported.
Long-term exposure to IL-17E causes multiorgan inflammation. The inflammatory infiltrate in IL-17E-TG mice is comprised of eosinophils; however, mixed cellular infiltrates, including neutrophils and lymphocytes, are frequently present and may result from secondary necrosis or induction of proinflammatory chemokines. Epithelial hyperplasia was observed in multiple tissues. Interestingly, the IL-17Rh1 message is elevated in multiple tissues in the TG mice, suggesting that the spectrum of tissues upon which IL-17E can act is influenced by the regulation of receptor expression. In a survey of human cell lines by PCR for expression of IL-17Rh1 mRNA, message was detectable in nearly all cell lines examined and was detectable in cells of various hemopoietic lineages (our unpublished observations). In this context, the complete mechanisms by which IL-17E promotes the development of inflammation and a Th2-immune profile are as yet unclear, but may reflect, at least partially, direct actions on cells of the immune system.
Microbial lipopeptides have recently been identified as the first demonstrated pathological inducers of IL-17 production (23). Lipopeptides are known to signal through the Toll-related receptor 2 (25, 26). This suggests that normal IL-17 function may relate the defense against pathogens. Consistent with this, IL-17R has recently been shown to be required for host defense against bacterial pneumonia (27). The immunological or pathological source of IL-17E remains to be identified, but IL-17E mRNA is expressed at very low levels in peripheral tissues (5). It is likely that there exist stimuli, as yet unidentified, that induce elevated expression of IL-17E. The phenotype of the IL-17E-TG mice also resembles an immune response to pathogens, with an inflammation marked by the presence of neutrophils, eosinophils, and macrophage, cells that are important mediators of innate host defense. It is conceivable that certain pathogens or their byproducts may be inducers of IL-17E production. In addition, the Th2 response can be considered a means of promoting humoral defense, a key component in the immune strategy against extracellular pathogens. In addition, histological changes in the lungs of TG mice suggest that IL-17E might contribute to the pathogenesis of allergy/asthma. It may be that both IL-17 and IL-17E and perhaps other members of the IL-17 family play roles in the generation and regulation of interactions between the adaptive and innate immune responses. The mIL-17E-TG mice developed diffuse interstitial and peribronchial inflammation with alveolar space filled with macrophages. It will be important to examine whether IL-17E contributes to the pathogenesis of allergy/asthma in human.
Although overexpression of IL-17E appears to drive a Th2-biased
response, increased expression of several Th1 cytokines (IFN- mRNA
and serum TNF-) was also seen in the TG mice. This might have been
from secondary tissue necrosis and contributed to the tissue-specific
variation in immunological response and pathological changes. Systemic
chronic exposure to IL-17E elicits inflammation in multiple organs;
however, it is conceivable that local expression of IL-17E in tissues
caused by certain disease conditions may induce a more localized,
tissue-specific immunological response and pathological changes. Future
efforts that aim at the identification of such disease conditions may
provide therapeutic opportunities.
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Acknowledgments |
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Footnotes |
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2 G.P. and D.F. share co-first authorship.
3 Abbreviations used in this paper: m, murine; TG, transgenic.
Received for publication July 25, 2001. Accepted for publication September 25, 2001.
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References |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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chemokine from mesothelial cells. J. Immunol. 165:5814.- and interleukin-4-induced activation of human keratinocytes. J. Invest. Dermatol. 115:81.[Medline]
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P. G. Fallon, S. J. Ballantyne, N. E. Mangan, J. L. Barlow, A. Dasvarma, D. R. Hewett, A. McIlgorm, H. E. Jolin, and A. N.J. McKenzie Identification of an interleukin (IL)-25-dependent cell population that provides IL-4, IL-5, and IL-13 at the onset of helminth expulsion J. Exp. Med., April 17, 2006; 203(4): 1105 - 1116. [Abstract] [Full Text] [PDF]
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Y. Maezawa, H. Nakajima, K. Suzuki, T. Tamachi, K. Ikeda, J.-i. Inoue, Y. Saito, and I. Iwamoto Involvement of TNF Receptor-Associated Factor 6 in IL-25 Receptor Signaling J. Immunol., January 15, 2006; 176(2): 1013 - 1018. [Abstract] [Full Text] [PDF]
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 K. Ikeda, H. Nakajima, K. Suzuki, S.-i. Kagami, K. Hirose, A. Suto, Y. Saito, and I. Iwamoto Mast cells produce interleukin-25 upon Fcepsilon RI-mediated activation Blood, May 1, 2003; 101(9): 3594 - 3596. [Abstract] [Full Text] [PDF]
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M. R. Kim, R. Manoukian, R. Yeh, S. M. Silbiger, D. M. Danilenko, S. Scully, J. Sun, M. L. DeRose, M. Stolina, D. Chang, et al. Transgenic overexpression of human IL-17E results in eosinophilia, B-lymphocyte hyperplasia, and altered antibody production Blood, September 18, 2002; 100(7): 2330 - 2340. [Abstract] [Full Text] [PDF]
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 S. Aggarwal and A. L. Gurney IL-17: prototype member of an emerging cytokine family J. Leukoc. Biol., January 1, 2002; 71(1): 1 - 8. [Abstract] [Full Text] [PDF]
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