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.     

In vitro electrophysiological effects of cimetidine, prostaglandin E2 and acetylcholine on the rabbit gastric mucosa

The electrophysiological effects of cimetidine, cytoprotective dose of prostaglandin E2 (PGE2) and acetylcholine were determined in parallel in Ussing-chambered rabbit fundic and antral mucosal preparations. In the fundic mucosal preparations both cimetidine and PGE2 caused an increase in transmucosal potential difference (PD) and in short-circuit current (ISC); the transepithelial resistance (Rt) was essentially unchanged. Addition of acetylcholine to the pretreated fundic preparations produced further gradual increases in PD and ISC; cimetidine pretreatment delayed this effect of acetylcholine. In contrast to fundic mucosa, cimetidine did not cause any electrical change of the antral preparation but decreases in PD, Rt and ISC were detected after the addition of PGE2. Acetylcholine produced a rapid initial PD elevation followed by a PD drop of both antral tissues independent of pretreatment. These findings suggest that both cimetidine and PGE2 generated electrical hyperpolarisation of rabbit fundic mucosa. These changes may be favourable for mucosal protection. No "beneficial" electrical changes were detected on the antral mucosa after administration of cimetidine and PGE2. Acetylcholine increased the effects of other stimuli on the fundic mucosa. In the rabbit antral mucosa acetylcholine generated biphasic changes of electrical properties.     

The role of IL-4 in Heligmosomoides polygyrus-induced alterations in murine intestinal epithelial cell function

IL-4 and IL-13 promote gastrointestinal worm expulsion, at least in part, through effects on nonlymphoid cells, such as intestinal epithelial cells. The role of IL-4/IL-13 in the regulation of intestinal epithelial function during Heligmosomoides polygyrus (Hp) infection was investigated in BALB/c mice infected with Hp or treated with a long-lasting formulation of recombinant mouse IL-4/alphaIL-4 complexes (IL-4C) for 7 days. Separate groups of BALB/c mice were drug-cured of initial infection and later reinfected and treated with anti-IL-4R mAb, an antagonist of IL-4 and IL-13 receptor binding, or with a control mAb. Segments of jejunum were mounted in Ussing chambers, and short circuit current responses to acetylcholine, histamine, serotonin, PGE2, and glucose were determined. Although only modest changes in epithelial cell function were observed during primary Hp infection, IL-4C or a secondary Hp infection each induced more dramatic changes, including increased mucosal permeability, reduced sodium-linked glucose absorption, and increased Cl- secretory response to PGE2. Some, but not all, effects of IL-4C and Hp infection were dependent on enteric nerves. Hp-induced changes in epithelial function were attenuated or prevented by anti-IL-4R mAb. Thus, IL-4/IL-13 mediate many of the effects of Hp infection on intestinal epithelial cell function and do so both through direct effects on epithelial cells and through indirect, enteric nerve-mediated prosecretory effects. These immune system-independent effector functions of IL-4/IL-13 may be important for host protection against gastrointestinal nematodes.     

Thromboxane receptors can modulate gastric acid secretion in the rat

The effects of PGE2 and the thromboxane A2 mimetic, U-46619, have been investigated on gastric secretion in the rat isolated gastric mucosa. Both compounds produced concentration-related inhibitions of histamine-induced secretion whereas only U-46619 inhibited methacholine-stimulated and basal secretion, and neither compound had any effect on the secretory response to dbcAMP. Indomethacin had no effect on the antisecretory activity of PGE2 but markedly reduced the potency of U-46619 suggesting that endogenous prostaglandins play a role in the U-46619 responses. However, direct inhibitory effects of U-46619 were seen at high concentrations. The thromboxane receptor antagonist AH23848, at concentrations selective for thromboxane receptors, had no effect on responses to PGE2 but markedly inhibited the effects of U-46619. We conclude that the antisecretory profile of U-46619 differs from that of PGE2. U-46619 has both direct and indirect antisecretory effects and these are mediated via thromboxane receptors in the rat gastric mucosa.     

Selective ablation of spinal afferent neurons containing CGRP attenuates gastric hyperemic response to acid.

The gastric mucosa, in particular submucosal blood vessels, are innervated by afferent neurons containing neuropeptides such as calcitonin gene-related peptide. Stimulation of sensory neurons innervating the gastric mucosa increases submucosal blood flow. Since sensory neurons supplying the stomach are of dual origin from nodose and dorsal root ganglia, we examined the effect of selective ablation of either the vagal or spinal sensory innervation to the upper gastrointestinal tract on the increase in gastric mucosal blood flow in response to acid back diffusion into the gastric mucosa. Perineural application of capsaicin to the celiac/superior mesenteric ganglia, but not to the vagus nerves, significantly inhibited by 53% the hyperemic response to acid back diffusion. Tissue levels of immunoreactive calcitonin gene-related peptide in the gastric corpus were significantly reduced (by 73%) by periceliac capsaicin treatment, but unaffected by perivagal capsaicin treatment. These data suggest that spinal capsaicin-sensitive afferents containing calcitonin gene-related peptide immunoreactivity are involved in mediating increases in gastric mucosal blood flow. This increase in gastric mucosal blood flow mediated by sensory neurons may act as a protective mechanism against mucosal injury, similar to responses seen in other tissues such as skin.     

Consequences of Epithelial Inflammasome Activation by Bacterial Pathogens

Inflammasome signaling impinges on the activation of inflammatory caspases (i.e., caspase-1 and caspase-4/5/11) and endows host cells with a sentinel system to sense microbial intrusion and thereby initiate appropriate immune responses. Lately, it has become evident that mammalian inflammasome-dependent responses to infection are not confined solely to cells of hematopoietic origin. Epithelial cells that line the body's mucosal surfaces use inflammasome signaling to sense and counteract pathogenic microorganisms that compromise barrier integrity. Many of the molecular mechanisms of epithelial inflammasome signaling remain unexplored. However, it now seems clear that epithelial inflammasome activation has a profound impact both on the infected cell itself and on its ability to communicate with other cell types of the mucosa. Here, we summarize current knowledge regarding the output of epithelial inflammasome activation during bacterial infection. Well-established downstream effects include epithelial cell death, release of soluble mediators, and subsequent recruitment of effector cell types, including NK cells, mast cells, and neutrophils, to sites of mucosal infection. We discuss the implications of recent findings for antibacterial defense in the mucosa and sketch out areas for future exploration.     

Injection of plasmid DNA into the gastric mucosa induces mucosal and systemic immunity

Nearly all mucosal surfaces participate in a common mucosal immune system, and application of an antigen to one mucosal surface elicits local as well as distant mucosal immune responses. However, whether the gastric mucosa is a part of this network has not been examined directly. We show here that the injection of plasmid DNA encoding beta-galactosidase into the gastric wall caused transfection of gastric mucosal epithelial cells, induced systemic and mucosal antibody responses at both local (digestive tract) and distant (genital and respiratory tracts) sites, and induced cytotoxic T lymphocyte responses in the spleen and the mesenteric and iliac lymph nodes.     

Effects of luminal thymol on epithelial transport in human and rat colon

Gut lumen is continually exposed to a great variety of agents, including noxious compounds. Chemical receptors that detect the luminal environment are thought to play an important role as sensors and to modulate gastrointestinal functions. Recently, it has been reported that odorant receptors (ORs) are expressed in the small intestinal mucosa and that odorants stimulate serotonin secretion. However, ion transport in the responses to odorants has rarely been discussed, particularly in relation to the large intestine. In the present study, we examined the effects of the OR ligand thymol on ion transport in human and rat colonic epithelia using an Ussing chamber. In the mucosal-submucosal preparations, the mucosal addition of thymol evoked anion secretion concentration dependently. In addition, dextran (4 kDa) permeability was enhanced by the mucosal treatment with thymol. The response to thymol was not affected by tetrodotoxin (TTX) or piroxicam treatments in human or rat colon. Thymol-evoked electrogenic anion secretion was abolished under Ca(2+)-free conditions or mucosal treatment with transient receptor potential (TRP) A1 blocker (HC-030031). Pretreatment of thymol did not affect electrical field stimulation-evoked anion secretion but significantly attenuated short-chain fatty acid-evoked secretion in a concentration-dependent manner. OR1G1 and TRPA1 expression was investigated in isolated colonic mucosa by RT-PCR. The present results provide evidence that the OR ligand thymol modulates epithelial permeability and electrogenic anion secretion in human and rat colon. The anion secretion by luminal thymol is most likely mediated by direct activation of TRPA1 channel. We suggest that the sensing and responding to odorants in the colon also plays a role in maintaining intestinal homeostasis.     

Sensory peptide neurotransmitters mediating mucosal and distension evoked neural vasodilator reflexes in guinea pig ileum

The aim was to determine the role CGRP and/or tachykinins released from sensory neural mechanisms in enteric neural vasodilator pathways. These pathways project through the myenteric plexus to submucosal vasodilator neurons. Submucosal arterioles were exposed in the distal portion of an in vitro combined submucosal-myenteric guinea pig ileal preparation, and dilation was monitored with videomicroscopy. Vasodilator neural reflexes were activated by gently stroking the mucosa with a fine brush or by distending a balloon placed beneath the flat-sheet preparation in the proximal portion. Dilations evoked by mucosal stroking were inhibited 64% by the CGRP 8-37 and 37% by NK3 (SR 142801) antagonists. When the two antagonists were combined with hexamethonium, only a small vasodilation persisted. Balloon distension-evoked vasodilations were inhibited by NK3 antagonists (66%) but were not altered by CGRP 8-37. In preparations in which myenteric descending interneurons were directly activated by electrical stimulation, combined application of CGRP 8-37 and the NK antagonists had no effect. Stimulation of capsaicin sensitive nerves in the myenteric plexus did not activate these vasodilator reflexes. These findings suggest that mucosal-activated reflexes result from the release of CGRP and tachykinins from enteric sensory neurons. Distension-evoked responses were significantly blocked by NK3 antagonists, suggesting that stretch activation of myenteric sensory neurons release tachykinins that activate NK3 receptors on myenteric vasodilator pathways.     

Effects of air flow on rat electroolfactogram

The electroolfactogram (EOG) previously has been used to demonstrate the regional distribution of rat olfactory epithelial odorant responses. Here, we evaluated the effects of airflow parameters on EOGs in two preparations: one where odorants were directly applied to the epithelium (opened preparation) and one where odorants were drawn through the nasal passages by an artificial sniff (closed preparation). EOG rise times served as one measure of odorant access. For isoamyl acetate (but not for limonene), rise times were slower in the lateral recesses of the closed (but not the opened) preparation. Polar odorants (amyl acetate, carvone and benzaldehyde) evoked smaller responses in the closed preparation than in the opened preparation, and these responses were particularly depressed in the lateral regions of the closed preparation. Responses to nonpolar hydrocarbon odorants (limonene and benzene) were equal in the lateral regions of both preparations, but were somewhat depressed in the medial region of the closed preparation. The responses to some polar odorants in the closed preparation were sensitive to changes in airflow parameters. These data suggest that the sorptive properties of the nose contribute substantially to determining the response of the epithelium and act to increase differences produced by inherent receptor mechanisms.     

Human alpha-calcitonin gene-related peptide influences colonic secretion by acting on myenteric neurons

The effect of human alpha-calcitonin gene-related peptide (CGRP) on epithelial ion transport was investigated in guinea pig distal colon set up in Ussing flux chambers. Addition of CGRP to the serosal bathing solution evoked a dose-dependent increase in short-circuit current in whole-thickness tissues with intact myenteric and submucosal ganglia, but not in whole-thickness preparations when neural connections between myenteric and submucosal ganglia were severed, nor in sheets of submucosa/mucosa with intact submucosal ganglia. The effects of CGRP were nearly abolished in chloride-free solutions or after treatment with furosemide. Tetrodotoxin and hexamethonium abolished the effects of CGRP on basal short-circuit current whereas atropine did not. CGRP enhanced neurally evoked chloride secretion both in whole thickness and submucosa/mucosa preparations, but the effect in the latter was considerably smaller. These observations suggest that CGRP stimulates chloride secretion primarily by activating myenteric neurons that project either to submucosal ganglia or to the mucosa of the guinea pig distal colon. Furthermore, CGRP appears to have a greater effect on excitability of myenteric neurons than submucosal neurons.     

Functional innervation of the myometrium of Myotis lucifugus, the little brown bat

Myometria of pregnant and nonpregnant Myotis lucifugus were studied in vitro by using electrical field stimulation as well as autonomic agonists and antagonists to determine whether functional responses corresponded with structural evidence showing abundant adrenergic and sparse cholinergic innervation, which uniquely does not disappear during pregnancy. Field stimulation (70 V, 0.6 ms, 5.0-s pulse train, 2.5 - 60 Hz) of myometria from nonpregnant (hibernating) bats produced graded responses consisting of an initial alpha-adrenergic contraction and a subsequent beta-adrenergic relaxation phase. Responses were sensitive to both the nerve poison tetrodotoxin and the adrenergic antagonist guanethidine, demonstrating that they resulted from stimulation of intrinsic adrenergic nerves. Field stimulation responses were unaffected by atropine indicating that there was no functional cholinergic innervation, even though carbachol-induced contraction showed that muscarinic receptors were present. In contrast, functional innervation of cervical tissue was cholinergic and nonadrenergic-non-cholinergic, but not adrenergic. At the beginning of active gestation, some myometrial preparations exhibited little of no response to field stimulation. However, as uterine size increased, the biphasic response to field stimulation was enhanced, particularly the inhibitory (beta-adrenergic) phase. Moreover, the contractile phases, though reduced, was not abolished by alpha-adrenergic antagonists. The residual contractile response was also tetrodotoxin-resistant, suggesting that the myometrium was sensitive to direct electrical stimulation. Near the end of pregnancy, myometrial tissue became nonresponsive to both field stimulation and autonomic agonists, suggesting an absence of available receptor sites on muscle cells.     

The role of mucosal immunity in prevention of HIV transmission

Vaccines designed to prevent mucosal transmission of HIV should establish multiple immune effectors in vaccine recipients, including antibodies which are capable of blocking HIV entry at mucosal epithelial barriers and of preventing initial infection of target cells in the mucosa. Immunological analyses of HIV-resistant humans and data obtained in nonhuman primate vaccine studies indicate that both secretory and serum antibodies may play an important role in protection against mucosal transmission of HIV or SIV, whereas cytotoxic T cells are required for clearance of mucosal infection and prevention of systemic spread. This review summarizes the roles of IgA and IgG antibodies in preventing mucosal infection by other viral and bacterial pathogens, and then discusses the various mechanisms by which antibodies might contribute to protection against HIV at mucosal surfaces. These include prevention of mucosal contact, blocking attachment of virus or infected cells to epithelial cells, interception of virus during transepithelial transport, neutralization of virus in the mucosa, and elimination of locally infected cells through antibody-dependent cell-mediated cytotoxic reactions. The regional nature of mucosal immune responses is reviewed in light of its relevance to HIV vaccine development. We conclude that mucosal immunization should be considered a component of vaccine strategies against HIV.     

Mucosal antibody responses of colonized cattle to Escherichia coli O157-secreted proteins, flagellin, outer membrane proteins and lipopolysaccharide

The aim of this work was to characterize adaptive mucosal immune responses to Escherichia coli O157:H7 at the principal site of colonization in the bovine species. Following experimental infection, extracts from terminal rectum mucosal samples were tested for IgA antibodies by immunoblotting against different bacterial antigens including: whole-cell E. coli O157:H7 with and without proteinase treatment, outer membrane and cytoplasmic preparations, secreted protein supernatants and purified E. coli O157 lipopolysaccharide and H7 flagellin. Lipopolysaccharide and H7 flagellin preparations were also used to coat enzyme-linked immunosorbent assay plates to determine mucosal IgG1 and IgA antibody titers. In this work, evidence is presented of strong local IgA immune responses induced following infection at the bovine terminal rectal mucosa directed against multiple antigens including type III secretion-dependent proteins, O157 lipopolysaccharide, H7 flagellin and OmpC.     

Sex-steroid-sensitive stromal cells and oviduct differentiation

The chick oviduct differentiates during sexual maturation before the age of 20 weeks. In the present work we used immunohistochemistry to study sexual maturation associated progesterone receptor (PR) expression in the chick oviduct as an indication of progesterone sensitivity. Since the PR is estrogen inducible protein, its expression also reflects the effects of endogenous estrogens. Thus PR expression can be used as a marker for action and sensitivity of cells to these sex steroids. In the luminal epithelium and mesothelium (peritoneal epithelium) the PR was expressed in high concentrations from the time before hatching (the constitutive PR). The PR was not detectable in stromal cells of immature chicks. At the age of 7-10 weeks the PR was detected in submucosal but not in mucosal stromal cells (the inductive PR). The appearance of these PR-expressing cells was associated with an increase in luminal epithelial cell proliferation. At the age of 14-16 weeks the mucosal plicae increased in height and the PR-expressing stromal cells were seen in the center of these mucosal plicae. There were also areas in the mucosal plicae where a large number of stromal cells expressing the PR were seen in the mucosal layer. Thereafter the size of the oviduct increased rapidly and the gland formation commenced. In the fully matured oviduct (over 18 weeks of age) virtually all stromal cells both in mucosa and submucosa expressed the PR. It is concluded that the PR expression in the luminal epithelium and mesothelium was constitutive (independent of sexual maturation). In stromal cells this was expressed during sexual maturation (probably induced by endogenous estrogen) and was associated with histological changes in the oviduct. We propose that direct effects of estrogen and progesterone in the oviduct growth and glandular formation are mediated through these stromal cells.     

EFFECTS OF CHRONIC STEROID INGESTION ON GASTRODUODENAL EPITHELIAL RENEWAL IN THE RAT

Steroids may predispose to peptic ulcer formation. One possible mechanism could be via alteration of normal epithelial renewal. to study the effects of steroids on gastroduodenal epithelial renewal, rats received hydrocortisone sodium succinate in the drinking water to deliver a dose of 10 mg/kg per day. Control rats received plain water. After 4 weeks, the rats were injected intraperitoneally with tritiated thymidine, to label proliferating cells, and killed 1 hr later, to determine measurements of epithelial proliferation, or 24 hr later to determine measurements of epithelial migration. Sections of fundus, antrum and post-pyloric duodenum were processed for light microscopy and autoradiography. In fundic and antral mucosa, steroid treatment resulted in a reduction in the number of labelled cells and in the size of the proliferative zone and, in the fundus, the mucosal thickness was reduced. In the duodenum, although the number of labelled cells remained unchanged, steroid treatment did decrease the number of cells in the proliferative zone; further, crypt depth was reduced in steroid-treated rats, but villous height was increased, resulting in an overall increase in mucosal thickness. Epithelial migration was also depressed in fundic and antral mucosa, but appeared to be accelerated in the duodenum of steroid-treated rats. These studies indicate that although, in the duodenum, the effects of steroids on epithelial renewal are complex, in the stomach chronic steroid ingestion depresses epithelial renewal both in fundic and antral mucosa. This inhibition of epithelial renewal in the stomach may contribute to the ulcerogenic action of steroids by either rendering the mucosa susceptible to the effects of other ulcerogens or by retarding the healing of existing mucosal lesions.     

TLR2, TLR3, and TLR4 activation specifically alters the oxidative status of intestinal epithelial cells

Intestinal inflammatory diseases are the result of multiple processes, including mucosal oxidative stress and perturbed homeostasis between commensal bacteria and mucosal immunity. Toll-like receptors (TLRs) recognize molecular-associated microorganisms' patterns and trigger innate immunity responses contributing to intestinal homeostasis and inflammatory responses. However, TLRs effects on redox balance in intestinal mucosa remain unknown. Therefore, the present study analyzes the effect of TLR2, TLR3, and TLR4 on both oxidative damage of lipids and proteins, and the activity of antioxidant enzymes in enterocyte-like Caco-2 cells. The results show that the activation of these TLRs increased lipid and protein oxidation levels; however, the effect on the antioxidant enzymes activity is different depending on the TLR activated. These results suggest that the activation of TLR2, TLR3, and TLR4 might affect intestinal inflammation by not only their inherent innate immunity responses, but also their pro-oxidative effects on intestinal epithelial cells.     

Prostaglandin E2 aggravates gastric mucosal injury induced by histamine in rats through EP1 receptors

We demonstrated that prostaglandin (PG) E2 aggravates gastric mucosal injury caused by histamine in rats, and investigated using various EP agonists which EP receptor subtype is involved in this phenomenon. Rats were used after 18 hr fasting. Histamine (80 mg/kg) dissolved in 10% gelatin, was given s.c., either alone or in combination with i.v. administration of PGE2 or various EP agonists such as 17-phenyl PGE2 (EP1), butaprost (EP2), sulprostone (EP1/EP3), ONO-NT012 (EP3) and ONO-AE1-329 (EP4). The animals were killed 4 hr later, and the mucosa was examined for lesions. The mucosal permeability was determined using Evans blue (1%). Histamine alone induced few lesions in the gastric mucosa within 4 hr. PGE2 dose-dependently worsened the lesions induced by histamine, the response being inhibited by tripelennamine but not cimetidine. The effect of PGE2 was mimicked by 17-phenyl PGE2 and sulprostone, but not other EP agonists, including EP2, EP3, and EP3/EP4 agonists. The mucosal vascular permeability was slightly increased by histamine, and this response was markedly enhanced by co-administration of 17-phenyl PGE2 as well as PGE2. The mucosal ulcerogenic and vascular permeability responses induced by histamine plus PGE2 were both suppressed by pretreatment with ONO-AE829, the EP1 antagonist. These results suggest that PGE2 aggravates histamine-induced gastric mucosal injury in rats. This action of PGE2 is mediated by EP1 receptors and functionally associated with potentiation of the increased vascular permeability caused by histamine through stimulation of H1-receptors.     

Pharmacologic methods for identification of receptors

Determinations of apparent equilibrium dissociation constants of drug-receptor interactions are made from both functional and radioligand binding studies. In each type of study, reversible reactions are assumed and the mass action law is applied. Functional studies are frequently used to determine the dissociation constant of a competitive antagonist but are less frequently used to obtain this constant for agonist compounds since the latter determination requires an experimental procedure that irreversibly inactivates a fraction of the receptors. In the present report, values of dissociation constant for prototype agonists and antagonists, determined from binding and from functional studies, are examined in two classical isolated preparations, rabbit aorta and guinea-pig ileum. In each preparation the dissociation constants from binding and functional experiments agree well for the antagonists but differ markedly for the agonists. Further, the dissociation constant values from binding are seen to be greater for the agonists than for the antagonists. When a chronic treatment regimen in the rabbit resulted in a pronounced change in the functional dissociation constant of subsequently administered norepinephrine, there was no significant change in either the binding constant of this agonist or in the pA2 value of the alpha antagonist, phentolamine. These, and the previously described results, are shown to be compatible with a simple two-state receptor model in which agonists bind with high and low affinity to each state while antagonists do not distinguish between the states. In this model, the ratio of low to high affinity states accounts for the failure of the binding procedure to detect changes in the agonists dissociation constant that are highly significant in the functional study. Whereas the model is based on data for these two classical preparations only, and may not be more generally applicable, the findings demonstrate the necessity for employing both functional and radioligand binding experiments when characterizing drug receptors.     

Activation of peroxisome proliferator-activated receptor gamma suppresses nuclear factor kappa B-mediated apoptosis induced by Helicobacter pylori in gastric epithelial cells

Helicobacter pylori colonization leads to epithelial cell hyperproliferation within inflamed mucosa, but levels of apoptosis vary, suggesting that imbalances between rates of cell production and loss may contribute to differences in gastric cancer risk among infected populations. Peroxisome proliferator-activated receptor gamma (PPARgamma) regulates inflammatory and growth responses of intestinal epithelial cells. We determined whether activation of PPARgamma modified H. pylori-induced apoptosis in gastric epithelial cells. PPARgamma was expressed and functionally active in gastric epithelial cell lines sensitive to H. pylori-induced apoptosis. PPARgamma ligands 15d-PGJ(2) and BRL-49653 significantly attenuated H. pylomicronri-induced apoptosis, effects that could be reversed by co-treatment with a specific PPARgamma antagonist. Cyclopentanone prostaglandins that do not bind and activate PPARgamma had no effects on H. pylori-induced apoptosis. The ability of H. pylori to activate nuclear factor (NF)-kappaB and increase levels of the NF-kappaB target IL-8 was blocked by co-treatment with PPARgamma agonists, and direct inhibition of NF-kappaB also abolished H. pylori-stimulated apoptosis. These results suggest that activation of the PPARgamma pathway attenuates the ability of H. pylori to induce NF-kappaB-mediated apoptosis in gastric epithelial cells. Because PPARgamma regulates a multitude of host responses, activation of this receptor may contribute to varying levels of cellular turnover as well as the diverse pathologic outcomes associated with chronic H. pylori colonization.