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,
Departments of
* Pediatrics,
Microbiology and Immunology, and
Medicine, Uniformed Services University of the Health Sciences, Bethesda, MD 20814;
Nutritional Requirements and Function Laboratory, Beltsville Human Nutrition and Research Center, Agricultural Research Service, U.S. Department of Agriculture, Beltsville, MD 20705; and
¶ Division of Immunology, Department of Medicine, University of Cincinnati, Cincinnati, OH 45267
 |
Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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). Binding of IL-4 by either
the type 1 or 2 IL-4R, or of IL-13 by the type 2 IL-4R, initiates
Jak-dependent tyrosine phosphorylation of the IL-4R-chain and the
transcription factor, STAT6. In the present study, we investigated: 1)
whether IL-13 has effects on intestinal epithelial cells similar to
those observed with IL-4, and 2) whether the effects of IL-4 and IL-13
depend on STAT6 signaling and/or mast cells. BALB/c,
STAT6-/-, and mast cell-deficient W/Wv mice
or their +/+ littermates were treated with a long-lasting formulation
of recombinant mouse IL-4 (IL-4C) or with IL-13 for seven days.
Segments of jejunum were mounted in Ussing chambers to measure mucosal
permeability; chloride secretion in response to PGE2,
histamine, 5-hydroxytryptamine, or acetylcholine; and
Na+-linked glucose absorption. IL-4C and IL-13 increased
mucosal permeability, decreased glucose absorption, and decreased
chloride secretion in response to 5-hydroxytryptamine. These effects
were dependent on STAT6 signaling. Responses to PGE2 and
histamine, which were dependent on mast cells and STAT6, were enhanced
by IL-4C, but not by IL-13. The effects of IL-4 and IL-13 on intestinal
epithelial cell function may play a critical role in host protection
against gastrointestinal nematodes. |
Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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IL-4 and IL-13 are of particular interest among the Th2 cytokines
elaborated in a type 2 response to nematode infection in that they
share several common biological properties, a functional overlap that
can be explained by the sharing of a common receptor or receptor
component (12). The type 1 IL-4R, which includes
IL-4R-chain and the cytokine receptor common 
-chain, is expressed
predominantly by bone marrow-derived cells and binds IL-4, but not
IL-13. The type 2 IL-4R, containing IL-4R-chain and IL-13R-chain,
is expressed predominantly by non-bone marrow-derived cells, and binds
both IL-4 and IL-13 (13). Binding of IL-4 (by either
receptor) or IL-13 (by the type 2 receptor) initiates
Jak-dependent tyrosine phosphorylation of
IL-4R-chain and the transcription factor, STAT6
(14, 15, 16). STAT6 is critical for the activation or
expression of many IL-4-responsive genes, including class II major
histocompatibility molecules, CD23, and the H chain gene for IgE
(17, 18, 19).
An integral component of the host response to enteric infection is to increase the fluid in the intestinal lumen in an effort to facilitate expulsion, limit access to the surface epithelia, and wash away potential deleterious agents (20). We showed previously that infection with gastrointestinal nematode Heligmosomoides polygyrus decreased glucose absorption and increased fluid secretion in response to the mast cell mediators histamine and PGE2, effects that were mediated by IL-4 (11). In the current studies, we investigated: 1) whether IL-13 has effects on intestinal epithelial cells similar to those observed with IL-4, and 2) whether the effects of IL-4 and IL-13 depend on mast cells and/or STAT6 signaling.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Male and female 8- to 12-wk-old BALB/c mice and mast cell-deficient W/Wv mice and their wild-type (WT) (+/+) littermates were purchased from The Jackson Laboratory (Bar Harbor, ME). STAT6-deficient (STAT6-/-) mice on a BALB/c background were bred at Uniformed Services University of the Health Sciences (Bethesda, MD), and were age and sex matched with controls in all experiments.4
Cytokines
Mice were given vehicle or IL-4, as described previously
(21), using a long-lasting IL-4 formulation (IL-4C),
consisting of 10 µg IL-4 (PeproTech, Rocky Hill, NJ) mixed with 50
µg 11B11, a neutralizing rat IgG1 anti-mouse IL-4 mAb (Verax,
Lebanon, NH). Anti-IL-4 mAb in this formulation is saturated with IL-4
to form complexes that contain a single mAb molecule and two IL-4
molecules. These complexes dissociate in vivo, releasing free IL-4 with
a t1/2 of 
1 day. Because these
complexes contain a single IgG molecule, they neither fix complement
nor bind more avidly than uncomplexed, monomeric IgG to FcRs.
Furthermore, because the mAb in these complexes blocks the binding of
IL-4 to its receptors, complexed IL-4 can only activate its receptor by
dissociating from the complex.
BALB/c or STAT6-/- mice were injected i.v. on days 0, 3, and 6 with IL-4C in 0.1 ml normal saline or with an equal volume of normal saline only, and were studied 7 days after the initial injection. Additional groups of mice were injected i.v. with 10 µg rIL-13 (Wyeth Research, Cambridge, MA) in 0.2 ml saline, or an equal volume of normal saline on days 0–6, and were studied 7 days after the initial injection.
Ussing chambers
Four 1-cm segments of mucosa were stripped of muscle and mounted in Ussing chambers that exposed 0.126 cm2 to 10 ml Krebs’ buffer. Agar-salt bridges and electrodes were used to measure potential difference. Every 50 s, the tissues were short circuited at 1 V (World Precision Instruments DVC 1000 voltage clamp, Sarasota, FL), and the short circuit current (Isc) was monitored continuously. In addition, every 50 s, the clamp voltage was adjusted to 1 V for 10 s to allow calculation of tissue resistance using Ohm’s law.
Following the 15-min equilibrium period, basal Isc, representing the net ion flux at baseline, and tissue resistance, a measure of tissue permeability, were determined. After a second 15-min period, concentration-dependent changes in Isc were determined for the cumulative addition of histamine, PGE2, 5-hydroxytryptamine (5-HT), or acetylcholine (ACH) to the serosal side of the stripped mucosae. After the peak response to the final concentration of each secretagogue was recorded, the Krebs’ buffer on each side of the chamber was replaced, and the tissue was allowed to equilibrate for 30 min. Upon re-equilibration, concentration-dependent changes in Isc were measured in response to the cumulative addition of glucose to the mucosal side. Responses from all tissue segments exposed to glucose from an individual mouse were averaged to yield a mean response per animal.
Solutions and drugs
Krebs’ buffer contained (in mM) 4.74 KCl, 2.54 CaCl2, 18.5 NaCl, 1.19 NaH2PO4, 1.19 MgSO4, and 25.0 NaHCO3 on each side. The tissues were allowed to equilibrate for 15 min in Krebs’ buffer containing 12 mM glucose on the serosal side and 10 mM mannitol on the mucosal side. All drugs were obtained from Sigma-Aldrich (St. Louis, MO), unless stated otherwise. Stock solutions of ACH (1 µM) were prepared in ultrapure water and frozen. PGE2 (1 µM) was dissolved in 100% ethanol and stored at -70°C. On the day of the experiment, 5-HT and histamine were dissolved in water, and appropriate dilutions of ACH, PGE2, 5-HT, histamine, and glucose were made using distilled water.
Histology
Tissue samples were prepared for visualization of MMC (10). Segments of midjejunum were excised, slit longitudinally, rolled, and placed immediately in Carnoy’s solution and fixed overnight. Tissues were then transferred to 95% ethanol, embedded in paraffin, and sectioned (5 µm). Deparaffinized sections were rehydrated and stained with Alcian blue and Safranin O (Polysciences, Warrington, PA). The numbers of MMC present in the lamina propria and mucosa were determined in 50 contiguous high-powered fields (magnification x400) in each section by an investigator who was unaware of the treatment group.
Data analysis
Statistical analysis was performed using one-way ANOVA to compare basal Isc and resistance. Cumulative dose responses were compared using multiple ANOVA with post hoc analysis for multiple comparisons. A value of p < 0.05 was considered significant.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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The effects of exogenous IL-13 or IL-4C on intestinal epithelial
cell resistance were evaluated in STAT6-/- and
WT mice. Resistance, a measure of tissue permeability, was similar in
untreated WT and STAT6- mice. In contrast,
resistance decreased significantly in WT, but not in
STAT6-/- mice, treated with IL-4C or IL-13
(Fig. 1
), demonstrating the STAT6
dependence of this response.
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To assess the effect of IL-13 or IL-4C on substrate-linked sodium
absorption, glucose was added to the mucosal (luminal) side of the
tissue. IL-4C and IL-13 significantly decreased
Isc responses to glucose in WT, but not in
STAT6-/- mice (Fig. 2), indicating the STAT6 dependence of
this effect.
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MMC were enumerated in STAT6-/- and WT
mice after 7 days of treatment with IL-4C or IL-13. Untreated
STAT6-/- and WT mice had similar numbers of MMC
(Fig. 3). MMC were significantly elevated
in both WT and STAT6-/- mice treated with
IL-4C; however, MMC in IL-4-treated STAT6-/-
mice were significantly lower than those in IL-4-treated WT mice (Fig. 3). IL-13 had no effect on MMC numbers in either WT or
STAT6-/- mice (Fig. 3).
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In contrast to STAT6-dependent effects of IL-4/IL-13 on intestinal
permeability and glucose absorption, IL-4C, but not IL-13, increased
Isc responses to PGE2 and
histamine in WT mice (Table I). Because
IL-4, but not IL-13, promotes intestinal mastocytosis (10)
(Fig. 3
), we determined whether the IL-4-induced increased
responsiveness of intestinal epithelium to PGE2
and histamine is mast cell dependent. This was accomplished by
comparing responses to PGE2 and histamine in WT
(+/+) and mast cell-deficient W/Wv mice after 7
days treatment with saline or IL-4C (Table II). Isc responses
to PGE2 and histamine were significantly enhanced
only in the IL-4C-treated +/+ mice, suggesting that these prosecretory
effects of IL-4 are mast cell dependent.
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), we
expected that the mast cell-dependent mechanism by which IL-4 increases
the response to histamine and PGE2 would also be
STAT6 independent. Surprisingly, although exogenous
PGE2 and histamine had similar effects on
intestinal epithelial secretory responses when added to the serosal
side of intestine from untreated WT and
STAT6-/- mice, in vivo IL-4C treatment enhanced
in vitro mucosal responses to PGE2 and histamine
in WT, but not in STAT6-/- mice (Fig. 4, A and B).
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To determine whether the effects of IL-4 on intestinal epithelial
cell responses to mediators of physiologic importance are universally
prosecretory, we also evaluated the effects of in vivo IL-4C treatment
on in vitro responses to 5-HT and ACH. In vivo treatment with IL-4
significantly inhibited Isc responses to 5-HT in
WT, but not in STAT6-/- mice (Fig. 5A). Effects on responsiveness
to 5-HT also differed from those observed
in response to PGE2 and histamine, in that they
were induced by in vivo treatment with IL-13 as well as by in vivo
treatment with IL-4 (Fig. 5B). In contrast to these positive
and negative effects on responsiveness to PGE2,
histamine, and 5-HT, neither IL-4 (79 ± 11
µA/cm2) nor IL-13 (81 ± 21
µA/cm2) had marked effects on in vivo
responsiveness to ACH when compared with controls (95 ± 8
µA/cm2).
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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In the current studies, we show that IL-4 and IL-13 induce similar
changes in epithelial cell resistance, absorption, and secretion, and
that these changes are STAT6 dependent. However, we also demonstrate
that IL-4, but not IL-13, increases prosecretory responses to
PGE2 and histamine, and that these effects are
mast cell dependent. Consistent with this finding, we show that IL-4,
but not IL-13, induces intestinal mastocytosis. The ability of IL-4,
but not IL-13, to induce intestinal mastocytosis in vivo is consistent
with a recent report by Suzuki et al. (26) that IL-4, but
not IL-13, promotes in vitro survival and growth of bone marrow-derived
mast cells and that the IL-4 effect requires ligation of the type 1
IL-4R (IL-4R/c), which binds IL-4, but not IL-13. Enhancement of
the secretory response to PGE2 may have a similar
explanation, because we do not see this response in mast cell-deficient
mice. Further evidence that differences between IL-4 and IL-13 effects
in our model are not explainable by lower relative concentrations of
IL-13 than IL-4 comes from our recent observation that IL-13 has a
considerably greater stimulatory effect than IL-4C, at the same doses
that were used in our manuscript, on intestinal smooth muscle
contractility (27).
These findings expand those of our previous report (11) in
two significant ways. First, our observation that IL-4 and IL-13 affect
the intestinal epithelial secretory response to 5-HT is novel, in that
it was not investigated in mice treated with anti-IL-4R mAb.
Second, and more importantly, our studies in the STAT6-deficient mice
demonstrate that this IL-4R-induced pathway is critical for a number of
the effects of IL-4 and/or IL-13 on intestinal mucosal physiology (Fig. 6). This latter observation was not an obvious consequence of the IL-4R
dependence of these effects, given that we had shown previously that
some important effects of IL-4R signaling, such as the induction of
mucosal mastocytosis and mast cell degranulation, were STAT6
independent (22).
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) and appear to conflict, in part, with others
(e.g., that 1) IL-4 treatment of the human intestinal cell line T84 in
vitro inhibits Cl- secretion (28, 29), and 2) IL-4/IL-13 induce a STAT6-independent,
phosphatidylinositol 3-kinase pathway-dependent, increased
transepithelial permeability in vitro in the human T84 intestinal cell
line (30)). This apparent conflict may be explained by the
in vivo administration of the cytokines in our study, as well as by
inherent differences in the function of homogeneous intestinal
epithelial cell lines vs excised intestinal mucosae with its intact
neural circuitry. However, it is of interest to note that two other
recent reports have shown 1) a dose-dependent decrease in the
resistance of rat glomerular visceral epithelial cells in vitro in
response to IL-4 or IL-13 (31), and 2) decreased
Na+ absorption and increased
Cl- secretion in vitro in response to IL-4
treatment of human bronchial epithelial cells (32).
Results of these studies suggest that the effects of IL-4 and IL-13 on
epithelial cell function may not be limited to the gastrointestinal
tract, but rather may represent a broader mechanism of immunoregulation
at epithelial cell surfaces.
More importantly, our observations indicate that the Th2 cytokines,
particularly IL-4 and IL-13, change intestinal epithelial function
through multiple effects that additively or synergistically interact to
shift the balance of ion and fluid flow toward the gut lumen, creating
the increase in luminal fluid that may protect the host against
pathogens. The complexity of these interactions is illustrated by the
IL-4 effects on intestinal responsiveness to PGE2
and histamine, which must have at least two components. The mast cell
dependence of this effect of IL-4 and its failure to be induced by
IL-13 (which does not stimulate mast cells) suggest that it requires
IL-4 stimulation of mastocytosis. However, IL-4 induction of mast cell
hyperplasia and mast cell degranulation (as measured by an increase in
serum levels of mouse mast cell protease) (22, 23) (Fig. 3) is STAT6 independent, while IL-4 enhancement of the prosecretory
effects of PGE2 and histamine is STAT6 dependent.
It remains to be determined whether STAT6 signaling is required to
induce mast cells to release specific mediators that promote increased
responsiveness to PGE2 and histamine, or whether
there is a separate, STAT6-dependent effect of IL-4 on intestinal
epithelial cells that acts with a STAT6-independent mast cell effect to
increase intestinal epithelial responsiveness. In support of the latter
possibility, IL-4 has been shown to act through a STAT6-dependent
mechanism to: 1) increase responsiveness to platelet-activating factor,
histamine, 5-HT, and leukotriene C4 in an
anaphylaxis model (33, 34); 2) induce increased expression
of a receptor for cysteinyl leukotrienes (35); and 3)
promote mast cell-dependent expulsion of Trichinella
spiralis by infected mice through an effect on non-bone
marrow-derived cells (24).
This difference in the effects of IL-4 and IL-13 on mast cells and mast cell-dependent epithelial function probably has consequences for host responses to intestinal worm infection and may explain differences in the relative importance of IL-4 and IL-13 in host protection against different parasites. Mice infected with N. brasiliensis do not require mast cells for parasite expulsion and exhibit a stronger dependence on IL-13 than IL-4 for worm expulsion (22). This greater dependence on IL-13 probably reflects either greater production of IL-13 than IL-4 by infected mice or increased potency of IL-13 vs IL-4 in the induction of a host-protective effect, because treatment of N. brasiliensis-infected mice with IL-4 induces worm expulsion in the absence of IL-13. In contrast, the mast cell-dependent expulsion of T. spiralis is more dependent on IL-4 than on IL-13, particularly during a second infection with this parasite (23). Thus, the secretion of both IL-4 and IL-13 during worm infections and the multiple mechanisms by which these cytokines promote changes in intestinal epithelial cell function appear to extend the ability of the Th2 cytokine response to protect against a spectrum of intestinal nematode parasites.
Finally, our observations demonstrate that not all effects of IL-4 and IL-13 on intestinal epithelial cells are prosecretory. Although 5-HT normally increases intestinal epithelial cell secretion, IL-4 and IL-13 inhibit this effect through a STAT6-dependent process. Furthermore, treatment of STAT6-/- and WT mice with IL-4C or IL-13 in vivo had no effect on the secretory response to ACH.
Thus, exposure to IL-4 and IL-13 shifts the relative importance of different mediators in regulating intestinal epithelial ion flow as well as the effects of specific mediators on this process. The role of inhibitory effects of IL-4/IL-13 on intestinal epithelial function, and the mechanisms by which inhibitory and stimulatory effects interact during parasite infection, remain to be determined.
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Acknowledgments |
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Footnotes |
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2 Address correspondence and reprint requests to Dr. Terez Shea-Donohue, Nutritional Requirements and Function Laboratory, Beltsville Human Nutrition and Research Center, Agricultural Research Service, U.S. Department of Agriculture, Beltsville, MD 20705. E-mail address: tshea{at}usuhs.mil
3 Abbreviations used in this paper: MMC, mucosal mast cell; 5-HT, 5-hydroxytryptamine; ACH, acetylcholine; Isc, short circuit current; WT, wild type.
4 These studies were conducted in accordance with the principles set forth in the Guide for Care and Use of Laboratory Animals, Institute of Laboratory Animal Resources, National Research Council, Health and Human Services Publication (National Institutes of Health) 85-23, revised 1996.
Received for publication May 10, 2002. Accepted for publication July 29, 2002.
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References |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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, and Stat6 are required for the expulsion of the gastrointestinal nematode parasite Nippostrongylus brasiliensis. Immunity 8:255.[Medline]
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RI-mediated late phase allergic responses of mast cells. J. Immunol. 168:421.This article has been cited by other articles:
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 T. L. Sutton, A. Zhao, K. B. Madden, J. E. Elfrey, B. A. Tuft, C. A. Sullivan, J. F. Urban Jr., and T. Shea-Donohue Anti-Inflammatory Mechanisms of Enteric Heligmosomoides polygyrus Infection against Trinitrobenzene Sulfonic Acid-Induced Colitis in a Murine Model Infect. Immun., October 1, 2008; 76(10): 4772 - 4782. [Abstract] [Full Text] [PDF]
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 E. E. Forbes, K. Groschwitz, J. P. Abonia, E. B. Brandt, E. Cohen, C. Blanchard, R. Ahrens, L. Seidu, A. McKenzie, R. Strait, et al. IL-9- and mast cell-mediated intestinal permeability predisposes to oral antigen hypersensitivity J. Exp. Med., April 14, 2008; 205(4): 897 - 913. [Abstract] [Full Text] [PDF]
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M. Khodoun, C. Lewis, J.-Q. Yang, T. Orekov, C. Potter, T. Wynn, M. Mentink-Kane, G. K. Khurana Hershey, M. Wills-Karp, and F. D. Finkelman Differences in Expression, Affinity, and Function of Soluble (s)IL-4R{alpha} and sIL-13R{alpha}2 Suggest Opposite Effects on Allergic Responses J. Immunol., November 15, 2007; 179(10): 6429 - 6438. [Abstract] [Full Text] [PDF]
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N. Nieuwenhuizen, D. R. Herbert, A. L. Lopata, and F. Brombacher CD4+ T Cell-Specific Deletion of IL-4 Receptor {alpha} Prevents Ovalbumin-Induced Anaphylaxis by an IFN-{gamma}-Dependent Mechanism J. Immunol., September 1, 2007; 179(5): 2758 - 2765. [Abstract] [Full Text] [PDF]
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 K. Minami, Y. Yanagawa, K. Iwabuchi, N. Shinohara, T. Harabayashi, K. Nonomura, and K. Onoe Negative feedback regulation of T helper type 1 (Th1)/Th2 cytokine balance via dendritic cell and natural killer T cell interactions Blood, September 1, 2005; 106(5): 1685 - 1693. [Abstract] [Full Text] [PDF]
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A. Pernthaner, S.-A. Cole, L. Morrison, and W. R. Hein Increased Expression of Interleukin-5 (IL-5), IL-13, and Tumor Necrosis Factor Alpha Genes in Intestinal Lymph Cells of Sheep Selected for Enhanced Resistance to Nematodes during Infection with Trichostrongylus colubriformis Infect. Immun., April 1, 2005; 73(4): 2175 - 2183. [Abstract] [Full Text] [PDF]
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H. D. Dawson, E. Beshah, S. Nishi, G. Solano-Aguilar, M. Morimoto, A. Zhao, K. B. Madden, T. K. Ledbetter, J. P. Dubey, T. Shea-Donohue, et al. Localized Multigene Expression Patterns Support an Evolving Th1/Th2-Like Paradigm in Response to Infections with Toxoplasma gondii and Ascaris suum Infect. Immun., February 1, 2005; 73(2): 1116 - 1128. [Abstract] [Full Text] [PDF]
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 D. Artis, M. L. Wang, S. A. Keilbaugh, W. He, M. Brenes, G. P. Swain, P. A. Knight, D. D. Donaldson, M. A. Lazar, H. R. P. Miller, et al. RELM{beta}/FIZZ2 is a goblet cell-specific immune-effector molecule in the gastrointestinal tract PNAS, September 14, 2004; 101(37): 13596 - 13600. [Abstract] [Full Text] [PDF]
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K. B. Madden, K. A. Yeung, A. Zhao, W. C. Gause, F. D. Finkelman, I. M. Katona, J. F. Urban Jr., and T. Shea-Donohue Enteric Nematodes Induce Stereotypic STAT6-Dependent Alterations in Intestinal Epithelial Cell Function J. Immunol., May 1, 2004; 172(9): 5616 - 5621. [Abstract] [Full Text] [PDF]
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, p < 0.05 vs WT IL-4C.
