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*
School of Biological Science, University of Manchester, Manchester; and
MRC (Medical Research Council) Laboratory of Molecular Biology, Cambridge, United Kingdom
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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There are exceptions, however; for example, expulsion of
Nippostrongylus brasiliensis from the mouse does not require
IL-4, as IL-4 KO mice expel the worms from the gut in a manner
equivalent to wild-type littermates (5). The mechanism of expulsion is
unknown but is unlikely to be mediated by a Th1 response, because in
all systems studied, promotion of a Th1 response is associated with
depression of the protective response and prolonged parasite survival.
Indeed, in the T. muris system, induction of a Th1 response
promotes chronic infection in a normally resistant strain of mouse (4, 6) and such a response becomes dominant in strains of mouse that
naturally harbor a chronic infection (7, 8). Interestingly, in the
latter system, neutralization of the protective IL-4 response in vivo
could only be achieved with anti-IL-4R mAb (M1) (4), but not
anti-IL-4 (either clones 11B11 or 1D11). Treatment with
anti-IL-4 mAb did however significantly reduce IgE levels and mast
cell numbers coincident with an increase in parasite-specific IgG2a
levels. IL-13, another Th2 cytokine, has been shown to utilize the
-chain of the IL-4 receptor. This finding raises the distinct
possibility that IL-13 may play an important role in the protective
process.
IL-13 is situated in close proximity to IL-4 on mouse chromosome 11.
Although the amino acid sequence homology between IL-4 and IL-13 is low
(
30%), there is a high level of conservation of the tertiary
structure between IL-4 and IL-13 (9). IL-13 shares many but not all of
the biologic functions of IL-4. IL-13 up-regulates a number of surface
markers (for example, MHC class II on monocytes and macrophages) while
down-regulating their production of inflammatory cytokines (10) and has
been shown to protect mice from LPS-induced lethal endotoxemia by
down-regulation of IFN-
(11). Unlike IL-4, IL-13 is not a T cell
growth factor, although it may influence T cell
development.4
Data presented here show that IL-13 does indeed play a critical role in resistance to T. muris. In the absence of IL-13, T. muris proceeds to a chronic infection. The IL-13 KO mouse is phenotypically different than the IL-4 KO mouse. Importantly, the data indicate that without IL-13, animals are unable to expel their worm burdens even in the presence of a strong Th2-type response. Futhermore, the data show that the absence of IL-13 interferes with the ability to regulate the magnitude of the Ag-specific isotype responses. These data do not negate an important role for IL-4 in resistance, as we clearly show that IL-4 KO mice are susceptible to T. muris. However, we believe this susceptibility is due to the inadequate production of Th2 cells and therefore the inability to produce Th2 cytokines, including IL-13.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Female age-matched C57BL/6 mice in groups of four, which had targeted disruption of the IL-4 gene (IL-4 KO), were purchased from B&K Universal (Hull, U.K.) as IL-4T. These mice were generated as previously described (12). The mice were originally produced on a 129 x C57BL/6 background, but have been subsequently backcrossed onto C57BL/6 six times. Age- and sex-matched C57BL/6 mice were used as wild-type controls.
129 mice that had a disrupted IL-13 gene (IL-13 KO mice) were generated as described in McKenzie et al.4 Age- and sex-matched IL-13 KO mice were used in groups of four to five. Wild-type 129 littermates were also used as wild-type controls.
Parasites
T. muris was maintained as described (13). Mice were killed at various time points after infection, and worm burdens were assessed as previously described (14).
Experimental protocol
Mice were infected on day 0 with approximately 300 T. muris eggs. On day 10, the viability of the infection was assessed. On days 14 or 21 postinfection (p.i.),5 mesenteric lymph node cells from infected and uninfected control IL-4 and IL-13 KO (and their wild-type littermates) were removed and set up in culture as described below. The mice were exsanguinated, and serum was prepared for Ab analysis. The cecum and adjacent colon were also removed to determine worm burdens. On day 35 p.i., only serum and parasitologic samples were taken.
Parasite Ag
Adult worms were cultured in RPMI 1640 (Gibco Life Technologies, Paisley, U.K.) and excretory-secretory Ag (ES) was collected over the first 4 h of culture. The ES was pelleted to remove parasite eggs, concentrated using Minicon-B15 concentrator (Amicon, Gloucester, U.K.), and then dialyzed against PBS. Protein concentration was determined using a Lowry assay (15) and added to cultures at a predetermined optimal concentration of 50 µg/ml.
Cytokine analysis
Mesenteric lymph node cells (MLNC) were removed from infected and control uninfected mice. MLNC were resuspended in RPMI 1640/10% FCS/2 mM L-glutamine, 1000 U/ml penicillin, and 1000 µg/ml streptomycin. They were stimulated with either 2.5 µg/ml of Con A or 50 µg/ml of parasite ES. Anti-IL-4R mAb (M1) was added to all cultures at a concentration of 5 µg/ml to increase the sensitivity of IL-4 detection. MLNC were cultured at 37°C and 5% CO2. Supernatants were collected at 24 h, pelleted to remove cells, and stored at -20°C until analyzed.
Cytokine analysis was conducted by sandwich ELISA using pairs of mAb.
For IL-4 (1D11 and 24G2), IL-5 (TRFK.5 and TRFK.4), and IFN- (R46A2
and XMG1.2), mAb were purchased from PharMingen (San Diego, CA). For
IL-9, 249.2, and 1C10/2C12 (J. van Snick, Ludwig Institute of Cancer
Research, Brussels, Belgium) were used. For IL-13, a commercially
available ELISA kit from R&D Systems (Minneapolis, MN) was used. The
amount of cytokine was determined by reference to commercially
available recombinant murine standards. The sensitivity of the assay
was determined by taking the mean + 3 SD of 16 control wells
containing medium alone.
Ab analysis
Parasite-specific IgG1 and IgG2a were conducted by ELISA as described (16). Briefly, Immulon IV plates (Dynatech, Denkendorff, Germany) were coated overnight with 5 µg/ml of ES in carbonate/bicarbonate buffer, pH 9.6, at 4°C. Following blocking (PBS/0.05% Tween 20, 3% BSA), serial twofold dilutions of serum were conducted from 1/20 to 1/2560 or 1/200 to 1/25600. Parasite-specific IgG1 and IgG2a Abs were detected using biotinylated rat anti-mouse IgG1 (Serotec) and biotinylated rat anti-mouse IgG2a (PharMingen).
Total serum IgE was determined also as described (16). Briefly, ELISA plates were coated with an anti-mouse IgE mAb (Serotec, Oxon, U.K.) and detected using a goat anti-mouse IgE polyclonal Ab conjugated to horseradish peroxidase (Nordic, Tilberg, The Netherlands). Quantification was made by reference to an IgE anti-dinitrophenol mAb (ICN, Bucks, U.K.).
Histology
At autopsy, the cecal tip was removed and fixed in Carnoys fixative before paraffin embedding. The embedded cecal tip was sectioned and stained for mast cells using 0.5% toluidine blue, pH 0.3. Numbers of mast cells were counted and expressed per 20 cecal crypt units.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Figure 1
shows worm burden data at
day 35 p.i. from IL-4 KO and wild-type C57BL/6 mice. It can
clearly be seen that IL-4 KO mice were susceptible to infection with
T. muris, whereas the wild-type C57BL/6 mice have expelled
the parasite. On day 32 p.i., female worms start to produce eggs,
which are shed in the feces, and then parasite transmission can take
place. Previous experiments have shown that later stages of the
parasite promote their own survival, and when the parasite has reached
adulthood it is not expelled from the gut without immune intervention
or anthelmintic treatment (17). Mice that have worms on day 35
p.i. are therefore termed susceptible and said to have a chronic
infection.
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Figure 2 shows cytokine production
from infected and uninfected IL-4 KO and wild-type C57BL/6 mice. MLNC
removed at day 21 p.i. were stimulated with 2.5 µg/ml of Con A.
This protocol, which has previously been used to analyze cytokine
production in strains of mouse that are resistant and susceptible to
T. muris, yields highly reproducible results (7, 8, 16).
Mice that lacked the IL-4 gene, in addition to making no IL-4 (Fig. 2A), made significantly reduced levels of other
Th2-type cytokines (IL-5, IL-9, and IL-13) (Fig. 2, B–D) in comparison with infected C57BL/6
mice (p < 0.05). This confirms that IL-4 is
necessary to make the Th2-type response associated with T.
muris infections in this strain of mouse. In contrast, IL-4 KO
mice made high levels of IFN-, a Th1-type cytokine (Fig. 2E), whereas infected (and resistant) C57BL/6 mice
made much lower levels of this cytokine.
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Figure 3, A and
B, shows parasite-specific IgG1 and IgG2a, respectively.
Figure 3A shows a level of parasite-specific IgG1 in
infected C57BL/6 mice typical of a resistant strain, whereas IL-4 KO
mice were unable to generate a detectable parasite-specific IgG1
response to infection. This is different from normally susceptible
strains of mouse, which usually generate a strong Th1 response (high
IgG2a) and a low but measurable parasite-specific IgG1 response (4).
Figure 3B shows that IL-4 KO mice made high levels of IgG2a.
This finding correlates well with the elevated levels of IFN-
observed after in vitro stimulation (Fig. 2
E), as the
the isotype switch to IgG2a is under the control of this cytokine (18).
The levels of parasite-specific IgG2a were comparable to those seen in
normally susceptible mouse strains. In comparison, infected C57BL/6
mice, which are resistant, made much lower levels of this Ab
isotype.
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Figure 4 shows worm burden data from
IL-13 KO mice and wild-type 129 littermates at day 35 p.i. Mice
that lack IL-13 were completely susceptible to infection, whereas
wild-type 129 mice had expelled their worms. 129 Wild-type mice readily
expel their worms; 43.85% of the established worm burden was expelled
between days 10 and 14 p.i., and a further 32.67% was lost
between days 14 and 21 p.i. (data not shown). By day 21, the
majority of the animals had completely expelled their parasites.
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Figure 5 shows cytokine production
from infected IL-13 KO mice and infected 129 wild-type mice. MLNC were
taken at day 14 p.i. and stimulated with 2.5 µg/ml Con A. Figure 5, A through D, demonstrates that, in addition to
making no IL-13, IL-13 KO mice made significantly reduced levels of
IL-4, IL-5, and IL-9 (p < 0.05) in comparison
with 129 wild-type mice. In contrast, IL-13 KO mice appeared to make
higher levels of IFN- (Fig. 5E) than 129 mice,
although this was not statistically significant.
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shows Ag-specific cytokine
production from infected and uninfected IL-13 KO mice taken at day
14 p.i. and stimulated with 50 µg/ml of parasite ES Ag. Cytokine
production mirrored that seen after Con A stimulation, although
absolute levels of cytokine were lower after specific stimulation. It
could again be seen that the IL-13 KO mice made significantly reduced
levels of Th2-type cytokines in comparison with 129 wild-type mice.
Levels of Ag-specific IFN- were not significantly different in
infected IL-13 KO mice (mean, 47.15 ± 9.7 U/ml) and infected 129
wild-type mice (mean, 31.3 ± 11.4 U/ml).
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shows Ag-specific cytokine
production at day 21 p.i. in IL-13 KO mice. Although IL-13 KO mice
produce no IL-13 (Fig. 7D), IL-4 and IL-5 production
(Fig. 7, A and B) was similar in infected
IL-13 KO mice and wild-type mice. Indeed, IL-9 production was actually
greater in IL-13 KO mice than in wild-type mice at this time point
(Fig. 7C). Interestingly, IFN- production was
significantly higher in infected IL-13 KO mice (131.24 ± 22.41
U/ml) than in infected wild-type mice (68.94 ± 23.39 U/ml) at
this time point.
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). Both mast cell production and IgE
production are associated with the production of a Th2-type
response (19, 20).
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Figure 9, A and
B, demonstrates the parasite-specific IgG1 and IgG2a Ab
response, respectively, in both infected and uninfected IL-13 KO and
129 mice. In contrast to the IL-4 KO mice, IL-13 KO mice made a high
level of parasite-specific IgG1 (Fig. 9A). The levels
of parasite-specific IgG1 seen in the infected 129 mice were typical
for resistant mice. The levels of parasite-specific IgG1 seen in the KO
mice were extremely high and did not titer out until a dilution of
1/25000 (data not shown). Figure 9B shows that IL-13 KO mice
also had very high levels of parasite-specific IgG2a. The 129 wild-type
mice had low levels of parasite-specific IgG2a with infection, typical
of this resistant phenotype. The levels of parasite-specific Ab (IgG1
and IgG2a) observed in the IL-13 KO mice exceeds that seen in previous
experiments with Trichuris.
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5-fold higher in infected IL-13 KO
mice than in infected 129 mice, with the greatest difference seen with
IgG2a, in which there was a 45-fold increase in IL-13 KO mice with
infection compared with wild-type mice (data not shown). |
Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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In vitro cytokine analysis of IL-4 KO mice revealed that upon infection
these animals have no IL-4 and very low levels of IL-5, IL-9, and IL-13
as well as an elevated level of IFN-. This was reflected in
parasite-specific isotype responses in vivo. The present data confirm
that IL-4 is important for the generation of Th2-mediated immunity in
response to T. muris and are consistent with studies of
other intestinal nematode infections in which this cytokine mediates
protective immunity (3). They also support the view that in the absence
of expansion of Th2 cells, levels of Th2 cytokines (including IL-13)
are inadequate to generate a protective response. IL-4, unlike IL-13,
influences T cell proliferation having an autocrine effect on Th2 cell
expansion (21). It has been proposed that IL-13 plays a role in Th2
cell differentiation.4 This may suggest that even if
IL-13-directed Th2 cell differentiation could take place in IL-4 KO
mice, expansion of a Th2 cell population would be unlikely to
occur.
The inability of IL-13 KO mice to expel T. muris demonstrates an important role for IL-13 in resistance to intestinal helminths, and although as yet we do not know the precise mechanism by which it acts, there are a number of possibilities. It has been proposed that IL-13 affects the differentiation of T cells along the Th2 pathway. It has previously been shown that the addition of exogenous IL-4 to in vitro cultures of T cells from IL-4 KO mice restored the production of IL-5 and IL-10 to levels comparable with those in wild-type mice (22). In similar experiments, however, using T cells from IL-13 KO mice, the addition of IL-4 had no such effect,4 suggesting that IL-13 may act upstream of IL-4 in Th2 cell development. Thus, the observed delay in the onset of cytokine responses (namely IL-4, IL-5, and IL-9 production) following T. muris infection in IL-13 KO mice is supportive of an important early role for IL-13 in the promotion of Th2-type responses. Eventual potentiation of the Th2-type response in IL-13 KO mice may reflect the action of additional non-T cell sources of IL-4, for example, mast cells. Certainly, bone marrow-derived mast cells from IL-13 KO mice have been shown to produce levels of IL-4 and IL-5 similar to those in wild-type mice mast cells upon stimulation in vitro.4 Indeed, our data confirm the ability of IL-13 KO mice to generate an intestinal mastocytosis coincident with an elevation of the Th2-type cytokine response, which can be seen most clearly by comparing in vitro cytokine production on day 21 p.i. in infected IL-13 KO mice. In vitro cytokine responses were reflected in vivo by elevated mast cell numbers, total IgE, and most strikingly, parasite-specific IgG1, which is in complete contrast to such responses in IL-4 KO mice.
The mechanism of IL-13-mediated protection remains to be defined, but
suggestions have been made in other systems. In a study in which rIL-13
was administered to mice given a lethal dose of LPS and protected from
endotoxic shock, there was a down-regulation of TNF-, IL-12, and
IFN- (11). Ablation of both the IL-12 and the IFN- response in
mice normally susceptible to T. muris induces resistance
through the induction of a Th2 response (our unpublished observations;
and 4 . Our present findings are consistent with the possibility
that IL-13 may act by down-regulating cytokines, including IFN- and
IL-12, following helminth infection.
It has also been suggested that IL-13 may contribute to the replenishment of effector cells during strong Th2 responses, as IL-13 has been shown to promote extramedullary hemopoiesis in mice similar to the responses observed when mice were infected with N. brasiliensis (23).
In contrast, IL-13 has been shown to enhance resistance to murine listeriosis (24), which shows a typical Th1-dominated immune response. More specifically, in that study it was demonstrated that IL-13 stimulated the production of IL-12 p40. Another study examined cytokine gene expression by in situ hybridization in patients with chronic atopic dermatitis and demonstrated coincident high levels of IL-12 and IL-13 (25). Nevertheless, most of the literature shows an inverse relationship between IL-12 and IL-13 production (11, 26).
Very little is known about the precise effector mechanisms involved in immunity to T. muris. A consistent finding is an important role for CD4+ T cells. The Th2-controlled eosinophilia and intestinal mastocytosis associated with resistance, however, are not essential but rather reflect the activation of a Th2-type response (reviewed in 27 . Other candidate mechanisms potentially controlled by CD4+ T cells include intestinal goblet cell responses and changes in turnover of intestinal epithelium. Certainly there are dramatic changes in both responses during Trichuris infection (D. Artis and W. I. Khan, unpublished observations), although the particular role that IL-13 plays remains to be explored.
The role of Ab in protection to T. muris is unclear.
Adoptive transfer studies have shown protective immunity can be
generated in SCID mice reconstituted with CD4+ T cells in
the complete absence of a B cell response (28). Furthermore, the data
presented here show that IL-13 KO mice are unable to expel their
parasites despite having extraordinarily high levels of
parasite-specific Ab in their serum. Indeed, these results indicate a
possible role for IL-13 in regulation of isotype responses in mice.
Whether this in an indirect effect through lack of control of other
cytokines (e.g., IFN-, IL-4, IL-6) or whether this is a direct
effect on B cells is unknown. This phenomenon may be related to a
regulatory role of IL-13 on IL-12 production, as reported by others
(29). Previous work in mice has demonstrated a significant increase in
serum IgG1 and IgG2a levels following in vivo administration of IL-12
(30). We have also observed similar effects on T.
muris-specific IgG2a and IgG1 responses following in vivo
treatment with IL-12 (6). Importantly, resistance to T.
muris can be induced in normally susceptible mice following in
vivo treatment with anti-IL-12 mAb (our unpublished data),
suggesting an important role for IL-12 in the natural progression to
chronic infection.
Finally, different inbred strains of mouse differ in their capacity to expel T. muris (31) and their ability to mount Th1 or Th2 responses (32, 33). Recent data have highlighted the effects of genetic backgrounds upon immune responses in KO mice (34, 35). Wild-type 129 expel T. muris rapidly and C57BL/6 at a slower rate, although both expel their parasites efficiently. We feel, therefore, that background strain considerations do not detract from the present data. We would suggest that IL-4 KO mice are susceptible because they cannot make a sufficient Th2 response; most importantly, they cannot make enough IL-13. IL-13 KO mice show that even in the presence of strong Th2-type responses, if no IL-13 is present, parasite expulsion is unlikely to take place. We cannot, however, rule out the possibility that IL-4 does play an important early effector role, as the IL-13 KO mice show a defect in early IL-4 production. It is clear, nevertheless, that IL-4 and IL-13 play important and distinct roles in resistance to T. muris.
Further evidence supporting an important role for IL-13 in resistance to intestinal helminths comes from N. brasiliensis infections in STAT 6 KO mice (3). IL-4 and IL-13 both signal through STAT 6, and unlike IL-4 KO mice, STAT 6 KO mice show a delayed expulsion of the parasite from the gut. The IL-13 KO mouse clearly reveals a unique phenotype and provides the ideal tool to further investigate the role of IL-13 in host parasite interactions and models of allergic inflammation.
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Acknowledgments |
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Footnotes |
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2 Address correspondence and reprint requests to Dr. Allison Bancroft, School of Biological Sciences, 3-239 Stopford Bldg., University of Manchester, Oxford Road, Manchester, U.K., M13 9PT. E-mail address:
3 A.N.J.M. and R.K.G. share senior authorship.
4 G. J. McKenzie, C. L. Emson, S. E. Bell, P. G. Fallon, M. Krishna, G. Zurawski, R. Murray, and A. N. J. McKenzie. Targeted disruption of the IL-13 gene in mice results in impaired T cell differentiation. Submitted for publication.
5 Abbreviations used in this paper: p.i., postinfection; ES, excretory-secretory; MLNC, mesenteric lymph node cells.
Received for publication October 15, 1997. Accepted for publication December 9, 1997.
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References |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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 A. R. Kitching, A. L. Turner, G. R.A. Wilson, K. L. Edgtton, P. G. Tipping, and S. R. Holdsworth Endogenous IL-13 Limits Humoral Responses and Injury in Experimental Glomerulonephritis but Does Not Regulate Th1 Cell-Mediated Crescentic Glomerulonephritis J. Am. Soc. Nephrol., September 1, 2004; 15(9): 2373 - 2382. [Abstract] [Full Text] [PDF]
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A. J. Bancroft, N. E. Humphreys, J. J. Worthington, H. Yoshida, and R. K. Grencis WSX-1: A Key Role in Induction of Chronic Intestinal Nematode Infection J. Immunol., June 15, 2004; 172(12): 7635 - 7641. [Abstract] [Full Text] [PDF]
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D. Negrao-Correa, D. G. Souza, V. Pinho, M. M. Barsante, A. L. S. Souza, and M. M. Teixeira Platelet-Activating Factor Receptor Deficiency Delays Elimination of Adult Worms but Reduces Fecundity in Strongyloides venezuelensis-Infected Mice Infect. Immun., February 1, 2004; 72(2): 1135 - 1142. [Abstract] [Full Text] [PDF]
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L. Spencer, L. Shultz, and T. V. Rajan T Cells Are Required for Host Protection against Brugia malayi but Need Not Produce or Respond to Interleukin-4 Infect. Immun., June 1, 2003; 71(6): 3097 - 3106. [Abstract] [Full Text] [PDF]
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M. L. deSchoolmeester, M. C. Little, B. J. Rollins, and K. J. Else Absence of CC Chemokine Ligand 2 Results in an Altered Th1/Th2 Cytokine Balance and Failure to Expel Trichuris muris Infection J. Immunol., May 1, 2003; 170(9): 4693 - 4700. [Abstract] [Full Text] [PDF]
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M. G. Chiaramonte, M. Mentink-Kane, B. A. Jacobson, A. W. Cheever, M. J. Whitters, M. E.P. Goad, A. Wong, M. Collins, D. D. Donaldson, M. J. Grusby, et al. Regulation and Function of the Interleukin 13 Receptor {alpha} 2 During a T Helper Cell Type 2-dominant Immune Response J. Exp. Med., March 17, 2003; 197(6): 687 - 701. [Abstract] [Full Text] [PDF]
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T. R. Johnson, R. A. Parker, J. E. Johnson, and B. S. Graham IL-13 Is Sufficient for Respiratory Syncytial Virus G Glycoprotein-Induced Eosinophilia After Respiratory Syncytial Virus Challenge J. Immunol., February 15, 2003; 170(4): 2037 - 2045. [Abstract] [Full Text] [PDF]
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 R. J. Dearman, C. J. Betts, N. Humphreys, B. F. Flanagan, N. J. Gilmour, D. A. Basketter, and I. Kimber Chemical Allergy: Considerations for the Practical Application of Cytokine Profiling Toxicol. Sci., February 1, 2003; 71(2): 137 - 145. [Abstract] [Full Text] [PDF]
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 L. Whittaker, N. Niu, U.-A. Temann, A. Stoddard, R. A. Flavell, A. Ray, R. J. Homer, and L. Cohn Interleukin-13 Mediates a Fundamental Pathway for Airway Epithelial Mucus Induced by CD4 T Cells and Interleukin-9 Am. J. Respir. Cell Mol. Biol., November 1, 2002; 27(5): 593 - 602. [Abstract] [Full Text] [PDF]
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D. Artis, S. Shapira, N. Mason, K. M. Speirs, M. Goldschmidt, J. Caamano, H.-C. Liou, C. A. Hunter, and P. Scott Differential Requirement for NF-{kappa}B Family Members in Control of Helminth Infection and Intestinal Inflammation J. Immunol., October 15, 2002; 169(8): 4481 - 4487. [Abstract] [Full Text] [PDF]
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N. E. Humphreys and R. K. Grencis Effects of Ageing on the Immunoregulation of Parasitic Infection Infect. Immun., September 1, 2002; 70(9): 5148 - 5157. [Abstract] [Full Text] [PDF]
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S. D. Hurst, T. Muchamuel, D. M. Gorman, J. M. Gilbert, T. Clifford, S. Kwan, S. Menon, B. Seymour, C. Jackson, T. T. Kung, et al. New IL-17 Family Members Promote Th1 or Th2 Responses in the Lung: In Vivo Function of the Novel Cytokine IL-25 J. Immunol., July 1, 2002; 169(1): 443 - 453. [Abstract] [Full Text] [PDF]
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L. R. Schopf, K. F. Hoffmann, A. W. Cheever, J. F. Urban Jr., and T. A. Wynn IL-10 Is Critical for Host Resistance and Survival During Gastrointestinal Helminth Infection J. Immunol., March 1, 2002; 168(5): 2383 - 2392. [Abstract] [Full Text] [PDF]
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H. Akiho, P. Blennerhassett, Y. Deng, and S. M. Collins Role of IL-4, IL-13, and STAT6 in inflammation-induced hypercontractility of murine smooth muscle cells Am J Physiol Gastrointest Liver Physiol, February 1, 2002; 282(2): G226 - G232. [Abstract] [Full Text] [PDF]
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L. Spencer, L. Shultz, and T. V. Rajan Interleukin-4 Receptor-Stat6 Signaling in Murine Infections with a Tissue-Dwelling Nematode Parasite Infect. Immun., December 1, 2001; 69(12): 7743 - 7752. [Abstract] [Full Text] [PDF]
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H. Helmby, K. Takeda, S. Akira, and R. K. Grencis Interleukin (IL)-18 Promotes the Development of Chronic Gastrointestinal Helminth Infection by Downregulating IL-13 J. Exp. Med., August 6, 2001; 194(3): 355 - 364. [Abstract] [Full Text] [PDF]
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N. M. Blackwell and K. J. Else B Cells and Antibodies Are Required for Resistance to the Parasitic Gastrointestinal Nematode Trichuris muris Infect. Immun., June 1, 2001; 69(6): 3860 - 3868. [Abstract] [Full Text] [PDF]
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W. I. Khan, B. A. Vallance, P. A. Blennerhassett, Y. Deng, E. F. Verdu, K. I. Matthaei, and S. M. Collins Critical Role for Signal Transducer and Activator of Transcription Factor 6 in Mediating Intestinal Muscle Hypercontractility and Worm Expulsion in Trichinella spiralis-Infected Mice Infect. Immun., February 1, 2001; 69(2): 838 - 844. [Abstract] [Full Text] [PDF]
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A. P. Mountford, K. G. Hogg, P. S. Coulson, and F. Brombacher Signaling via Interleukin-4 Receptor {alpha} Chain Is Required for Successful Vaccination against Schistosomiasis in BALB/c Mice Infect. Immun., January 1, 2001; 69(1): 228 - 236. [Abstract] [Full Text] [PDF]
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H. N. Ehigiator, A. W. Stadnyk, and T. D. G. Lee Extract of Nippostrongylus brasiliensis Stimulates Polyclonal Type-2 Immunoglobulin Response by Inducing De Novo Class Switch Infect. Immun., September 1, 2000; 68(9): 4913 - 4922. [Abstract] [Full Text] [PDF]
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J. Urban, H. Fang, Q. Liu, M. J. Ekkens, S.-J. Chen, D. Nguyen, V. Mitro, D. D. Donaldson, C. Byrd, R. Peach, et al. IL-13-Mediated Worm Expulsion Is B7 Independent and IFN-{gamma} Sensitive J. Immunol., April 15, 2000; 164(8): 4250 - 4256. [Abstract] [Full Text] [PDF]
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M. D. Taylor, C. J. Betts, and K. J. Else Peripheral Cytokine Responses to Trichuris muris Reflect Those Occurring Locally at the Site of Infection Infect. Immun., April 1, 2000; 68(4): 1815 - 1819. [Abstract] [Full Text] [PDF]
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 A. Heinzmann, X.-Q. Mao, M. Akaiwa, R.T. Kreomer, P.-S. Gao, K. Ohshima, R. Umeshita, Y. Abe, S. Braun, T. Yamashita, et al. Genetic variants of IL-13 signalling and human asthma and atopy Hum. Mol. Genet., March 1, 2000; 9(4): 549 - 559. [Abstract] [Full Text] [PDF]
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P. G. Fallon, E. J. Richardson, G. J. McKenzie, and A. N. J. McKenzie Schistosome Infection of Transgenic Mice Defines Distinct and Contrasting Pathogenic Roles for IL-4 and IL-13: IL-13 Is a Profibrotic Agent J. Immunol., March 1, 2000; 164(5): 2585 - 2591. [Abstract] [Full Text] [PDF]
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B. Johansson, S. Ingvarsson, P. Bjorck, and C. A. K. Borrebaeck Human Interdigitating Dendritic Cells Induce Isotype Switching and IL-13-Dependent IgM Production in CD40-Activated Naive B Cells J. Immunol., February 15, 2000; 164(4): 1847 - 1854. [Abstract] [Full Text] [PDF]
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J. F. Urban Jr., L. Schopf, S. C. Morris, T. Orekhova, K. B. Madden, C. J. Betts, H. R. Gamble, C. Byrd, D. Donaldson, K. Else, et al. Stat6 Signaling Promotes Protective Immunity Against Trichinella spiralis Through a Mast Cell- and T Cell-Dependent Mechanism J. Immunol., February 15, 2000; 164(4): 2046 - 2052. [Abstract] [Full Text] [PDF]
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 M. Richard, R. K. Grencis, N. E. Humphreys, J.-C. Renauld, and J. Van Snick Anti-IL-9 vaccination prevents worm expulsion and blood eosinophilia in Trichuris muris-infected mice PNAS, January 18, 2000; 97(2): 767 - 772. [Abstract] [Full Text] [PDF]
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F. P. Heinzel and R. A. Maier Jr. Interleukin-4-Independent Acceleration of Cutaneous Leishmaniasis in Susceptible BALB/c Mice following Treatment with Anti-CTLA4 Antibody Infect. Immun., December 1, 1999; 67(12): 6454 - 6460. [Abstract] [Full Text] [PDF]
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D. Artis, N. E. Humphreys, A. J. Bancroft, N. J. Rothwell, C. S. Potten, and R. K. Grencis Tumor Necrosis Factor {alpha} Is a Critical Component of Interleukin 13–mediated Protective T Helper Cell Type 2 Responses during Helminth Infection J. Exp. Med., October 4, 1999; 190(7): 953 - 962. [Abstract] [Full Text] [PDF]
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 T. R. Johnson and B. S. Graham Secreted Respiratory Syncytial Virus G Glycoprotein Induces Interleukin-5 (IL-5), IL-13, and Eosinophilia by an IL-4-Independent Mechanism J. Virol., October 1, 1999; 73(10): 8485 - 8495. [Abstract] [Full Text] [PDF]
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A. L. Dent, T. M. Doherty, W. E. Paul, A. Sher, and L. M. Staudt BCL-6-Deficient Mice Reveal an IL-4-Independent, STAT6-Dependent Pathway That Controls Susceptibility to Infection by Leishmania major J. Immunol., August 15, 1999; 163(4): 2098 - 2103. [Abstract] [Full Text] [PDF]
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J. Poudrier, P. Graber, S. Herren, D. Gretener, G. Elson, C. Berney, J.-F. Gauchat, and M. H. Kosco-Vilbois A Soluble Form of IL-13 Receptor {alpha}1 Promotes IgG2a and IgG2b Production by Murine Germinal Center B Cells J. Immunol., August 1, 1999; 163(3): 1153 - 1161. [Abstract] [Full Text] [PDF]
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D. Jankovic, M. C. Kullberg, N. Noben-Trauth, P. Caspar, J. M. Ward, A. W. Cheever, W. E. Paul, and A. Sher Schistosome-Infected IL-4 Receptor Knockout (KO) Mice, in Contrast to IL-4 KO Mice, Fail to Develop Granulomatous Pathology While Maintaining the Same Lymphokine Expression Profile J. Immunol., July 1, 1999; 163(1): 337 - 342. [Abstract] [Full Text] [PDF]
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M. Mohrs, B. Ledermann, G. Kohler, A. Dorfmuller, A. Gessner, and F. Brombacher Differences Between IL-4- and IL-4 Receptor {alpha}-Deficient Mice in Chronic Leishmaniasis Reveal a Protective Role for IL-13 Receptor Signaling J. Immunol., June 15, 1999; 162(12): 7302 - 7308. [Abstract] [Full Text] [PDF]
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N. Noben-Trauth, W. E. Paul, and D. L. Sacks IL-4- and IL-4 Receptor-Deficient BALB/c Mice Reveal Differences in Susceptibility to Leishmania major Parasite Substrains J. Immunol., May 15, 1999; 162(10): 6132 - 6140. [Abstract] [Full Text] [PDF]
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L. Cohn, R. J. Homer, H. MacLeod, M. Mohrs, F. Brombacher, and K. Bottomly Th2-Induced Airway Mucus Production Is Dependent on IL-4R{alpha}, But Not on Eosinophils J. Immunol., May 15, 1999; 162(10): 6178 - 6183. [Abstract] [Full Text] [PDF]
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G. Grünig, M. Warnock, A. E. Wakil, R. Venkayya, F. Brombacher, D. M. Rennick, D. Sheppard, M. Mohrs, D. D. Donaldson, R. M. Locksley, et al. Requirement for IL-13 Independently of IL-4 in Experimental Asthma Science, December 18, 1998; 282(5397): 2261 - 2263. [Abstract] [Full Text]
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I-C. Ho, D. Lo, and L. H. Glimcher c-maf Promotes T Helper Cell Type 2 (Th2) and Attenuates Th1 Differentiation by Both Interleukin 4-dependent and -independent Mechanisms J. Exp. Med., November 16, 1998; 188(10): 1859 - 1866. [Abstract] [Full Text] [PDF]
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H. Faulkner, J.-C. Renauld, J. Van Snick, and R. K. Grencis Interleukin-9 Enhances Resistance to the Intestinal Nematode Trichuris muris Infect. Immun., August 1, 1998; 66(8): 3832 - 3840. [Abstract] [Full Text] [PDF]
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