Biomedical subjects

Kathleen B Madden

Publications and source records attributed to Kathleen B Madden.

10 recordsLinked to original sources

PubMed2006

Functional importance of regional differences in localized gene expression of receptors for IL-13 in murine gut.

IL-13 induces a STAT6-dependent hypercontractility of intestinal smooth muscle that is mediated by binding to the IL-13Ralpha1 component of the type 2 IL-4R that is linked to STAT6. IL-13 also binds to the IL-13Ralpha2 that is not linked to STAT6 and functions to limit the effects of IL-13 in vivo. In this study we assessed the contributions of regional and cellular differences in the distribution of the IL-13R components to the physiological regulation of smooth muscle function in wild-type mice and mice deficient in STAT6 or IL-13Ralpha2. The expression of IL-13 and IL-13Ralpha2 was higher in colon than in small intestine. Laser capture microdissection of specific cell types revealed that the expression of IL-13Ralpha2 was higher in the smooth muscle layer compared with levels in the epithelial cells of the mucosa. In contrast, there was a uniform distribution of IL-13alpha1 in smooth muscle, epithelia, and myenteric neurons. The significant hypercontractility of smooth muscle in mice deficient in IL-13Ralpha2, but not in STAT6, shows the physiological importance of IL-13 binding to IL-13Ralpha2. The pronounced differences in the expression of IL-13Ralpha2 suggest that the gut has developed sophisticated mechanisms for controlling the physiological and pathophysiological activities of IL-13.

Animals↗

PubMed2006

Contribution of 5-HT2A receptor in nematode infection-induced murine intestinal smooth muscle hypercontractility.

BACKGROUND & AIMS: Enteric nematode infection induces a smooth muscle hypercontractility that depends on interleukin (IL)-4 and IL-13 activation of the signal transducer and activator of transcription (STAT) 6. Serotonin (5-HT) is involved in the physiologic regulation of gut function. The present study investigated the contribution of 5-HT and its receptors in nematode-induced intestinal smooth muscle hypercontractility. METHODS: Mice were infected with Nippostrongylus brasiliensis (N brasiliensis) or Heligmosomoides polygyrus (H polygyrus) or injected intravenously with IL-13. Segments of jejunum were suspended in organ baths, and smooth muscle responses to 5-HT were determined in the presence or absence of specific 5-HT antagonists. IL-4, IL-13, and 5-HT receptor messenger RNA expressions were determined by real-time quantitative polymerase chain reaction. RESULTS: 5-HT evoked a modest contraction of smooth muscle in wild-type (WT) mice that was unaltered by the 5-HT2A antagonist ketanserin. N brasiliensis infection induced a smooth muscle hypercontractility to 5-HT that was abolished by 5-HT(2A) antagonists but not by other 5-HT antagonists. Infection-induced up-regulation of 5-HT2A expression was correlated with the smooth muscle hypercontractility to 5-HT. The infection-induced up-regulation of 5-HT2A in WT mice was observed also in IL-4(-/-) mice but was not seen in IL-13(-/-) or STAT6(-/-) mice. In addition, smooth muscle responses to 5-HT and 5-HT2A expression in WT mice were also enhanced by IL-13 or H polygyrus infection. CONCLUSIONS: These data show that 5-HT2A is one of the molecules downstream from STAT6 activation that mediates changes in smooth muscle function. 5-HT2A represents a novel therapeutic target for modulating immune-mediated effects on intestinal motility.

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PubMed2005

Immune regulation of protease-activated receptor-1 expression in murine small intestine during Nippostrongylus brasiliensis infection.

Infection with gastrointestinal nematodes exerts profound effects on both immune and physiological responses of the host. Helminth infection induces a hypercontractility of intestinal smooth muscle that is dependent on the Th2 cytokines, IL-4 and IL-13, and may contribute to worm expulsion. Protease-activated receptors (PARs) are expressed throughout the gut, and activation of PAR-1 was observed in asthma, a Th2-driven pathology. In the current study we investigated the physiologic and immunologic regulation of PAR-1 in the murine small intestine, specifically 1) the effect of PAR-1 agonists on small intestinal smooth muscle contractility, 2) the effects of Nippostrongylus brasiliensis infection on PAR-1 responses, 3) the roles of IL-13 and IL-4 in N. brasiliensis infection-induced alterations in PAR-1 responses, and 4) the STAT6 dependence of these responses. We demonstrate that PAR-1 activation induces contraction of murine intestinal smooth muscle that is enhanced during helminth infection. This hypercontractility is associated with an elevated expression of PAR-1 mRNA and protein. N. brasiliensis-induced changes in PAR-1 function and expression were seen in IL-4-deficient mice, but not in IL-13- or STAT6-deficient mice, indicating the dependence of IL-13 on the STAT6 signaling pathway independent of IL-4.

Animals↗

PubMed2005

Impact of vitamin E or selenium deficiency on nematode-induced alterations in murine intestinal function.

The effects of deficiencies in the antioxidant nutrients, vitamin E and selenium, on the host response to gastrointestinal nematode infection are unknown. The aim of the study was to determine the effect of antioxidant deficiencies on nematode-induced alterations in intestinal function in mice. BALB/c mice were fed control diets or diets deficient in selenium or vitamin E and the response to a secondary challenge inoculation with Heligmosomoides polygyrus was determined. Egg and worm counts were assessed to determine host resistance. Sections of jejunum were mounted in Ussing chambers to measure changes in permeability, absorption, and secretion, or suspended in organ baths to determine smooth muscle contraction. Both selenium and vitamin E deficient diets reduced resistance to helminth infection. Vitamin E, but not selenium, deficiency prevented nematode-induced decreases in glucose absorption and hyper-contractility of smooth muscle. Thus, vitamin E status is an important factor in the physiological response to intestinal nematode infection and may contribute to antioxidant-dependent protective mechanisms in the small intestine.

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PubMed2005

Deficiencies in selenium and/or vitamin E lower the resistance of mice to Heligmosomoides polygyrus infections.

Previous studies have shown that deficiencies in selenium (Se) and/or vitamin E (VE) can exacerbate the infectivity and pathogenesis of coxsackievirus B3 and influenza. Both Se and VE play a role in immune function and antioxidant defense. To determine whether these deficiencies would affect the normal course of infection with a metazoan parasite, mice were made deficient in Se and/or VE and inoculated with the gastrointestinal nematode parasite Heligmosomoides polygyrus. Both primary and secondary infections were assessed. Although the course of a primary infection with H. polygyrus was unaffected by diet, diets deficient in Se, VE, and both Se and VE (Se/VE double-deficiency) all caused delayed adult worm expulsion and increased fecundity during a secondary infection; suggesting an impaired intestinal response. H. polygyrus-induced IL-4 levels were diet-independent; but Se/VE double-deficiency blocked the H. polygyrus-induced IL-4 receptor-associated decrease in sodium-dependent glucose absorption in the jejunum that contributes to worm expulsion. In contrast, Se/VE double-deficiency had no effect on the infection-induced, IL-4R-associated increase in epithelial cell permeability that accompanies the infection. These results suggest that both Se and VE are required for specific IL-4-related changes in intestinal physiology that promote host protection against H. polygyrus.

Animals↗

PubMed2005

Localized multigene expression patterns support an evolving Th1/Th2-like paradigm in response to infections with Toxoplasma gondii and Ascaris suum.

Human infectious diseases have been studied in pigs because the two species have common microbial, parasitic, and zoonotic organisms, but there has been no systematic evaluation of cytokine gene expression in response to infectious agents in porcine species. In this study, pigs were inoculated with two clinically and economically important parasites, Toxoplasma gondii and Ascaris suum, and gene expression in 11 different tissues for 20 different swine Th1/Th2-related cytokines, cytokine receptors, and markers of immune activation were evaluated by real-time PCR. A generalized Th1-like pattern of gene expression was evident in pigs infected with T. gondii, along with an increased anti-inflammatory gene expression pattern during the recovery phase of the infection. In contrast, an elevated Th2-like pattern was expressed during the period of expulsion of A. suum fourth-stage larvae from the small intestine of pigs, along with low-level Th1-like and anti-inflammatory cytokine gene expression. Prototypical immune and physiological markers of infection were observed in bronchial alveolar lavage cells, small intestinal smooth muscle, and epithelial cells. This study validated the use of a robust quantitative gene expression assay to detect immune and inflammatory markers at multiple host tissue sites, enhanced the definition of two important swine diseases, and supported the use of swine as an experimental model for the study of immunity to infectious agents relevant to humans.

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PubMed2004

Enteric nematodes induce stereotypic STAT6-dependent alterations in intestinal epithelial cell function.

Infection with gastrointestinal nematodes exerts profound effects on both the immune and physiological responses of the host. We showed previously that the Th2 cytokines, IL-4 and IL-13, induce STAT6-dependent changes in intestinal epithelial cell permeability, absorption, and secretion that are similar to those observed in a secondary infection with Heligmosomoides polygyrus. In the current study we investigated whether nematode-induced effects on epithelial cell function were 1) generic, 2) dependent upon STAT6, and 3) attributable to direct effects on the epithelial cells themselves or mediated by effects on enteric nerves. Our results demonstrate that infection of BALB/c mice with three different gastrointestinal nematodes (H. polygyrus, Nippostrongylus brasiliensis, and Trichinella spiralis) alters intestinal epithelial cell function by decreasing resistance, glucose absorption, and secretory responses to 5-hydroxytryptamine and acetylcholine, two critical mediators in the submucosal reflex pathway. These modified responses are dependent on STAT6 and are the result of both direct effects and indirect effects mediated through enteric nerves.

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PubMed2004

Interleukin-4- and interleukin-13-mediated host protection against intestinal nematode parasites.

Intestinal worm infections characteristically induce T-helper 2 cell (Th2) cytokine production. We reviewed studies performed with mice infected with either of two intestinal nematode parasites, Nippostrongylus brasiliensis or Trichinella spiralis, that evaluate the importance of the Th2 cytokine interleukin-4 (IL-4) and IL-13 in protection against these parasites. These studies demonstrate that while IL-4/IL-13 protect against both parasites by activating signal transducer and activator of transcription 6 (Stat6) through IL-4 receptor alpha (IL-4Ralpha) ligation, Stat6 activation protects against these parasites through different mechanisms. Stat6-dependent gene transcription promotes expulsion of N. brasiliensis solely through effects on non-bone marrow-derived cells that may include enhancement of intestinal smooth muscle contractility, changes in intestinal epithelial cell function, and increased intestinal mucus secretion. In contrast, Stat6 signaling promotes immunity to T. spiralis both through effects on bone marrow-derived cells that can be reproduced by treating mice with IL-4 or IL-13 and through effects on non-bone marrow-derived cells. The former effects appear to include T-cell-dependent induction of intestinal mastocytosis, while the latter sensitize non-bone marrow-derived cells to mast cell-produced mediators. We argue that a limited ability of the host immune system to distinguish among different nematode parasites has led to the evolution of a stereotyped Th2 response that activates a set of effector mechanisms that protects against most intestinal nematode parasites.

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PubMed2003

Dependence of IL-4, IL-13, and nematode-induced alterations in murine small intestinal smooth muscle contractility on Stat6 and enteric nerves.

IL-4 and IL-13 promote gastrointestinal worm expulsion in part through effects on nonlymphoid cells, such as intestinal smooth muscle cells. The roles of Stat6 in IL-4-, IL-13-, and parasitic nematode-induced effects on small intestinal smooth muscle contractility were investigated in BALB/c wild-type and Stat6-deficient mice treated with a long-lasting formulation of recombinant mouse IL-4 (IL-4C) or IL-13 for 7 days. Separate groups of BALB/c mice were infected with Nippostrongylus brasiliensis or were drug-cured of an initial Heligmosomoides polygyrus infection and later reinfected. Infected mice were studied 9 and 12 days after inoculation, respectively. Segments of jejunum were suspended in an organ bath, and responses to nerve stimulation and to acetylcholine and substance P in the presence and absence of tetradotoxin, a neurotoxin, were determined. Both IL-4 and IL-13 increased smooth muscle responses to nerve stimulation in wild-type mice, but the effects were greater in IL-13-treated mice and were absent in IL-13-treated Stat6-deficient mice. Similarly, hypercontractile responses to nerve stimulation in H. polygyrus- and N. brasiliensis-infected mice were dependent in part on Stat6. IL-13, H. polygyrus, and N. brasiliensis, but not IL-4, also increased contractility to acetylcholine by mechanisms that involved Stat6 and enteric nerves. These studies demonstrate that both IL-4 and IL-13 promote intestinal smooth muscle contractility, but by different mechanisms. Differences in these effects correlate with differences in the relative importance of these cytokines in the expulsion of enteric nematode parasites.

Acetylcholine↗

PubMed2002

Role of STAT6 and mast cells in IL-4- and IL-13-induced alterations in murine intestinal epithelial cell function.

Gastrointestinal nematode infections generally invoke a type 2 cytokine response, characterized by the production of IL-4, IL-5, IL-9, and IL-13. Among these cytokines, IL-4 and IL-13 exhibit a functional overlap that can be explained by the sharing of a common receptor or receptor component (IL-4Ralpha). 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-4Ralpha-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/W(v) 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 PGE(2), 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 PGE(2) 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.

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