Prostaglandin E₂ (PGE₂) plays a role in the pathogenesis of gastro-esophageal reflux disease (GERD). There are 4 subtypes of PGE₂, PGE₂ receptor 1, 2, 3 and 4 (EP 1-4). In GERD patents, PGE₂, EP2 and EP4 are upregulated. However, the effects of PGE2 on esophageal motility remain elusive. We examined how PGE₂ regulates motility in the porcine circular smooth muscle of the lower esophageal sphincter (LES), and the circular and longitudinal smooth muscle of the esophagus body in organ bath. PGE₂ induced tonic relaxation in the LES and circular smooth muscle, but transient contraction in longitudinal smooth muscle. The relaxation of the LES and circular smooth muscle was similar in pattern and mechanism, but was much larger in the LES. The relaxation was completely blocked by a voltage-gated K⁺ channel blocker or 40 mM K⁺ depolarization, indicating the involvement of K⁺ channel. Longitudinal smooth muscle contraction was completely blocked by an L-type Ca²⁺ channel blocker, showing the contribution of Ca²⁺ movement. The involvement of the EP receptor in motility was examined with selective receptor agonists and antagonists. Activation of EP2 and EP4 caused relaxation in the LES and circular smooth muscle. Compatible with PGE₂, EP2 and EP4 agonists caused more significant relaxation in the LES than in circular smooth muscle. EP1 contributed to the longitudinal smooth muscle contraction. The different effects of PGE₂ in the LES, circular and longitudinal smooth muscle contributes to esophageal motility, their impairment might increase the amount and frequency of esophageal reflux.

The aim of this study was to determine which PGE2 receptors (EP1-4 receptors) influence colonic motility. Mucosa-free longitudinal smooth muscle strips of the rat middle colon spontaneously induced frequent phasic contractions (giant contractions, GCs) in vitro, and the GCs were almost completely abolished by a cyclooxygenase inhibitor, piroxicam, and by an EP3 receptor antagonist, ONO-AE3-240, but enhanced by tetrodotoxin (TTX). In the presence of piroxicam, exogenous PGE2, both ONO-AE-248 (EP3 agonist), and ONO-DI-004 (EP1 agonist) induced GC-like contractions, and increased the frequency and amplitude. These effects of EP receptor agonists were insensitive to TTX and ω-conotoxins. In immunohistochemistry, the EP1 and EP3 receptors were expressed in the longitudinal smooth muscle cells. These results suggest that the endogenous PGE2 spontaneously generates and enhances the frequent phasic contractions directly activating the EP1 and EP3 receptors expressed on longitudinal smooth muscle cells in the rat middle colon.

Mice lacking the pertussis toxin-sensitive G-protein subunit Gi alpha2 spontaneously develop colitis and colon cancer. In the gut, arachidonate-derived prostaglandin E2 (PGE2) modulates intestinal immune responses and epithelial restitution and is derived largely from subepithelial myofibroblasts.

We tested whether known decreases in arachidonate release in cells lacking Gi alpha2 would result in decreased PGE2 production and tissue PGE2 levels. PGE2 levels were significantly decreased in the colon of Gi alpha2-/- mice.

Gi alpha2-/- myofibroblasts from the small intestine and colon both released asymptotically equal to 50% less arachidonate and 3- to 7-fold less PGE2 and 6-keto PGF1alpha in response to adenosine triphosphate, thrombin, tumor necrosis factor-alpha, or lipopolysaccharide, in a partially cyclooxygenase (COX)-2-dependent manner. Decreased arachidonate release did not appear to be caused by a defect in cPLA2 translocation in the absence of Gi alpha2. Basal myofibroblast COX-1 and COX-2 expression was downregulated in Gi alpha2-/- cells. No differences in proliferation rates were found between serum-starved or serum-activated wild-type (WT) and Gi alpha2-/- myofibroblasts. Finally, treatment of Gi alpha2-/- mice with the EP4-specific PGE2 receptor agonist ONO-AE1-329 significantly decreased the severity of established colitis.

These findings confirm a requirement for Gi alpha2 in intestinal and colonic myofibroblast-derived prostanoid production and confirm the importance of mucosal PGE2 in the suppression of colitis.

The small bowel is an important dose-limiting organ in abdominal radiotherapy because irradiation can cause acute enteritis that, in turn, leads to progressively reduced motility and finally, in a later phase, to fibrosis. Because these clinical symptoms may be caused by the early stage of an inflammatory process, we characterized the radiation-induced intestinal inflammation in rats. Abdominal gamma-irradiation (10-Gy) induced a cascade of inflammatory events characterized by an early (6 h after exposure) increase in IL-1beta, TNF-alpha, and IL-6 mRNA levels in the rat ileal muscularis layer. IL-8 [a cytokine-induced neutrophil chemoattractant (CINC)] mRNA appeared later (at 3 days). The expression of TGF-beta (a profibrotic cytokine) was higher in irradiated than control tissue at day 1, whereas IL-10 (an anti-inflammatory cytokine) expression vanished completely. Despite strong IL-1ra expression, the IL-1ra/IL-1beta ratio, which is an indicator of inflammatory balance, was -41% at day 1 in irradiated compared with control tissue. The nuclear transcription factors NF-kappaB and activator protein-1 (AP-1) govern transcription of these genes, directly or indirectly. Although expression of the subunits of NF-kappaB (p65, p50) and AP-1 (c-fos, c-jun) did not increase, irradiation caused a rapid and persistent translocation of p65 and p50. An imbalance between proinflammatory and anti-inflammatory mediators may contribute to perpetuating intestinal inflammation, thus making it chronic.

In contrast to most other disorders of the digestive system, functional disorders of the gut continue to be defined by symptom criteria rather than by biological markers. At the same time, animal models of functional gastrointestinal disorders in which to test pathophysiologic hypotheses are lacking. The aim of this report is to critically review recently proposed conceptual as well as animal models of functional gastrointestinal disorders. Converging disease models have been proposed that postulate an enhanced responsiveness of neural, immune, or neuroimmune circuits in the central nervous system or in the gut to exteroceptive (psychosocial) or interoceptive (tissue irritation, inflammation, infection) perturbations of the organism's homeostasis. The enhanced responsiveness results in dysregulation of gut motility, epithelial function (immune, permeability), and visceral hypersensitivity, which in turn produce irritable bowel syndrome symptoms. These conceptual models provide plausible mechanisms for irritable bowel syndrome symptom generation and are consistent with extensive epidemiologic and pathophysiologic data. Several animal models have recently been proposed that mimic key features of these conceptual disease models. They fall into models triggered by centrally targeted stimuli (neonatal stress, post-traumatic stress disorder) or those triggered by peripherally targeted stimuli (infection, inflammation). Depending on the timing of the trigger (neonatal vs. adult), the changes induced in the animal may be permanent or transient. Future development of existing and novel models involves the use of transgenic and knockout animals, as well as the demonstration of predictive validity in terms of responsiveness to candidate drugs.

Chronic abdominal symptoms develop in some patients after acute enteric infection. This study examined mechanisms underlying smooth muscle hypercontractility that persists after acute infection in mice.

Euthymic and athymic National Institutes of Health (NIH) Swiss mice were infected with Trichinella spiralis and studied 4 weeks postinfection (PI). Isometric tension was assessed in longitudinal muscle. Cytokine and cyclooxygenase (COX)-2 messenger RNA was determined in the muscularis externa by reverse-transcription polymerase chain reaction. COX-2 protein was identified by immunohistochemistry and prostaglandin E(2) was measured by enzymatic immunoassay. Studies were performed in euthymic and athymic NIH Swiss mice 28 days PI and in the presence or absence of treatment with corticosteroid or COX inhibitors.

Muscle hypercontractility was evident in euthymic mice but was attenuated in athymic mice or in steroid-treated euthymic mice 28 days PI. Expression of Th2 cytokines interleukins 4, 5, and 13 was increased during the acute infection but not thereafter. COX-2 was localized to muscle and its enzymatic activity remained significantly increased in the muscle on day 28 PI. Selective COX-2 inhibition in vitro reduced the sustained increase in tension generation.

These findings show that COX-2 activation in resident cells of the muscularis externa contributes to the muscle hypercontractility that persists after infection.

Changes in gastric emptying and orocaecal transit time in patients with ulcerative colitis suggest that disturbances in gut motility may not be restricted to inflamed sites. This study sought to characterize changes in the motility of noninflamed ileum in a rat colitis model and to explore the mechanism(s) potentially involved. The myoelectrical activity of the ileum was recorded in rats with trinitrobenzene sulphonic acid (TNBS)-induced colitis. The degree of ileal and colonic inflammation was assessed by quantification of macroscopic damage and myeloperoxidase activity (MPO). The effect on ileal motility of pretreatment with atropine, indomethacin and NG-nitro-L-arginine-methyl ester (L-NAME) was investigated. TNBS-induced inflammation was restricted to the distal colon, as evidenced by morphological scores and MPO. Colitis was associated with increased frequency of ileal migrating motor complexes, characterized mainly by a decrease in the duration of phases I and III. The occurrence of ileal giant migrating complexes remained unchanged. The myoelectrical changes observed in the ileum persisted after treatment with atropine, indomethacin and L-NAME. Distal colitis is associated with abnormal myoelectrical activity in the noninflamed ileum of rats. Neither acetylcholine nor prostaglandins and nitric oxide seem to be involved.

Cytokine production by resident cells of the richly innervated muscularis externa may contribute to neuromuscular changes observed during intestinal inflammation. This study investigated neurotransmitter modulation of cytokine production by intestinal smooth muscle.

We measured interleukin (IL)-6 messenger RNA expression by reverse-transcription polymerase chain reaction, IL-6 by bioassay, and cyclic adenosine monophosphate by enzyme immunoassay in rat cultured intestinal smooth muscle cells exposed to IL-1beta, in the presence or absence of neurotransmitters.

IL-1beta significantly increased IL-6 messenger RNA and protein. This was dose-dependently enhanced by vasoactive intestinal polypeptide (VIP), calcitonin gene-related peptide (CGRP), and norepinephrine and inhibited by [LYS1,PRO2,5,ARG3,4,TYR6]VIP and propranolol, respectively. Forskolin mimicked the stimulatory effects of these neurotransmitters on IL-6 secretion, and the protein kinase inhibitor6-22 amide abolished the actions of VIP, CGRP, and norepinephrine, but not that of human recombinant IL-1beta, on IL-6 secretion. These agents each increased cyclic adenosine monophosphate activity in muscle substance P, and the neurokinin 1 agonist Ac-[Arg6,Sar9,Met(O2)11] substance P(6-11) inhibited the IL-1beta-induced IL-6 release.

This study shows neuropeptide and sympathetic modulation of IL-1beta-induced IL-6 production by intestinal smooth muscle. These interactions may contribute to altered muscle function during intestinal inflammation.

The increased expression of several cytokines, including interleukin 6 (IL-6), has recently been reported in a study of the longitudinal muscle and myenteric plexus layers of rat intestine following Trichinella spiralis infection. However, the putative cellular sources and the mechanism underlying the induction of IL-6 in these tissues are presently unknown. The aim of this study was to examine the ability of cultured smooth muscle cells from rat jejunum to produce IL-6 messenger RNA and protein and to investigate the underlying mechanism.

Cultured smooth muscle cells were treated with human recombinant interleukin 1 beta (HrIL-1 beta). The level of IL-6 messenger RNA was estimated by polymerase chain reaction, and the released IL-6 protein was estimated by bioassay.

HrIL-1 beta induced IL-6 messenger RNA expression in the smooth muscle cells in a time- and concentration-dependent manner. This was accompanied by the secretion of IL-6 protein into the medium. The effect of HrIL-1 beta was blocked by the IL-1 receptor antagonist, by actinomycin D, or by prior boiling of the cytokine.

These findings show that HrIL-1 beta interacts with its receptor on smooth muscle cells to induce transcription of the IL-6 gene and to cause the secretion of IL-6. These results indicate that intestinal smooth muscle cells are not only targets for but also a source of cytokine.

Colitis may be induced in animals by oral administration of sulfated polysaccharides (carrageenan, amylopectin sulfate, dextran sulfate), chemical irritation by rectal instillation of diluted acetic acid, delayed hypersensitivity reaction after sensitization to DNCB or after one single administration of TNBS, and Arthus reaction induced by intravenous injection of immune complexes after chemical irritation of the colon, and by chemoattractant peptides such as FMLP. It appears that all models of colon inflammation in the rat, mouse, or rabbit produce increased amounts of eicosanoids similar to that found in human colitis. Thus, animal studies provide useful information on the origin, regulation, and function of inflammatory mediators. However, with the possible exception of the cotton-top tamarin, no animal model of induced or spontaneous inflammation of the colon is analogous to human ulcerative colitis in etiology, course of disease activity, or histology (114). The observation that two different immune-mediated models gave similar results suggests that the colitis is not a specific response to delayed-type hypersensitivity or immune-complex-mediated reactions but rather an unspecific, stereotype response (125). The original disturbance may not determine the nature of the lesions ultimately produced but may instead serve as an initiator of a final common immunologic pathway.

The aim of this study was to assess the effect of cell culture on the bradykinin receptor of rabbit colon myocytes. In longitudinal muscle strips prepared from distal colon, bradykinin stimulated dose-dependent contraction that was 62% of the maximal response to bethanecol. At 4 degrees C, [3H]bradykinin binding to fresh muscle homogenates from the distal colon was time dependent, saturable, and linearly related to tissue concentration. Specific binding of 0.6 nmol/L [3H]bradykinin was 80% +/- 2% of total binding. In competitive binding studies, Hill coefficients approached unity, suggesting the presence of a single class of receptors. The order of potency was bradykinin greater than [D-Phe7]bradykinin much greater than des-Arg9, [Leu8]bradykinin, which is consistent with results of a B2 receptor subclass. Colon myocytes from the longitudinal muscle layer achieved confluence and were harvested for studies after 12-14 days in culture. Bradykinin receptors were of high affinity [disassociation constant (Kd) = 672 pmol/L] and numbered 10,217 +/- 2567/cell. To show that the receptors on cultured myocytes were functional, the effect of bradykinin was measured (a) on intracellular calcium concentration using Fura 2 and (b) on prostaglandin E2 concentration in the culture media using radioimmunoassay. In cells grown to confluence on cover slips and preloaded with Fura 2, bradykinin stimulated the threshold response at 1 nmol/L and maximal response (increased intracellular calcium concentration from 229 to 633 nmol/L) at 1 mumol/L. Bradykinin, 100 nmol/L, increased Prostaglandin E2 in the culture media threefold. In summary, colon myocytes express functioning bradykinin receptors, which, unlike muscarinic receptors, persist in culture. Bradykinin appears to be a suitable agonist for studies of receptor-mediated intracellular events in cultured colon myocytes.

The symptoms of urgency, diarrhea, and abdominal discomfort are exaggerated after a meal in inflammatory disorders of the colon, such as ulcerative colitis. The possible motor correlates of these symptoms were investigated in a model of acute colitis in six dogs. Each dog was instrumented with seven strain gauge transducers, two on the proximal, three on the middle, and two on the distal colon. After an overnight fast, 4-hour fasted recordings were made from the normal colon and after the colon had been cleansed on the previous day with Colyte (Reed & Carnrick, Piscataway, NJ). A 1300-kcal meal was then fed, and the recordings were continued for another 8 hours. Acute colitis was then induced by the perfusion of 10 mL of 75% acetic acid and confirmed with colonoscopy and biopsy. The fasted and postprandial recordings were repeated during the next 5 days. In the control state, ingestion of the meal increased the total duration per hour of contractile activity in the early (0-2 hours) and late (2-8 hours) postprandial periods in the distal colon. In the proximal and the middle colon, a significant increase in motor activity occurred only during the late postprandial period. Similar effects were observed in the cleansed colon. By contrast, there was no significant increase in motor activity after a meal during colitis in any of the postprandial periods in the cleansed or the uncleansed colon. During colitis, there was a significant increase in the incidence of giant migrating contractions in the fasted state. The ingestion of a meal further increased the frequency of giant migrating contractions in the uncleansed colon from 0.4 +/- 0.1 to 1.3 +/- 0.5 per hour in the late postprandial period. There was no significant increase during the early postprandial period. The increase in the late postprandial frequency of giant migrating contractions was associated with an increase in defecation frequency. It is concluded that the motor response of the colon to a meal is absent in acute colitis. The entry of new ingesta into the colon during the late postprandial period stimulates enteric mechanisms to initiate an excessive number of giant migrating contractions. These giant migrating contractions may be related to increased postprandial abdominal discomfort and increased frequency of defecation.

Prostaglandins exhibit a variety of actions on intestinal smooth muscle depending upon the type, dose and muscle layer studied. As the cellular origin of prostaglandin H (PGH) synthase has not been established with certainty in the human gut wall, we studied the localization of PGH synthase in the human duodenum, jejunum, ileum and colon by immunohistochemistry. PGH synthase immunoreactivity appeared to be similar in all segments of the intestine. Most smooth muscle cells seemed to contain PGH synthase; however, the reaction in the lamina muscularis mucosae was much stronger than in the longitudinal and circular muscle layers. Endothelial cells in capillaries and larger vessels showed a positive reaction. In addition, unidentified cells in subserosa, at the level of Auerbach's plexus and in the submucosa were stained. We concluded that the smooth muscle cells of the human gut has a rather large capacity for PGH synthesis and the present results may provide a basis for a better understanding of both normal physiological functions as well as intestinal disease states involving disorders of prostaglandin synthesis.

Although the specific cause(s) of inflammatory bowel diseases (IBD) has not been identified, one theory suggests ischemia as the early event that occurs in IBD and reperfusion causes sustained release of oxyradicals, leading to inflammation and ulceration. In this study, we have confirmed that H2O2 in the concentration seen during ischemia/reperfusion is primarily responsible for cellular membrane damage in the rat colonic fragments in vitro. Hydrogen peroxide caused a time and dose-dependent increase in 6-keto-PGF1 alpha and TXB2 release. Hydrogen peroxide-stimulated 6-keto-PGF1 alpha release was blocked (50%) by phospholipase A2 (PLA2) inhibitors quinacrine and dimethyleicosadienoic acid at 5 min. Hydrogen peroxide-stimulated 6-keto-PGF1 alpha release was completely blocked by indomethacin, significantly blocked (69%) by nordihydroguiaretic acid, and completely blocked by catalase. Superoxide dismutase and uric acid failed to inhibit H2O2-stimulated 6-keto-PGF1 alpha release. Endogenous catalase inhibitors 3-aminotriazole and sodium azide further enhanced the release of 6-keto-PGF1 alpha stimulated by H2O2 by 29% and 73%, respectively. Xanthine-xanthine oxidase also increased 6-keto-PGF1 alpha release from the fragments by 110%. This release was not inhibited by superoxide dismutase and uric acid, but was completely inhibited by catalase. These studies suggest a direct effect of H2O2 on colonic fragments leading to submicroscopic cellular membrane damage and excess prostanoid production utilizing a PLA2/cyclooxygenase and catalase-sensitive pathway without the formation of toxic hydroxyl ions. The quick release of 6-keto-PGF1 alpha also suggests an early manifestation of H2O2-induced damage in rat colonic fragments.

Interleukin 1 or 3 added to the serosal side of chicken small intestine transiently increases short-circuit current. Replacement of bathing-medium Cl and HCO3 with gluconate and HEPES abolished the short-circuit current increase, consistent with these cytokines stimulating electrogenic anion secretion. Cytokine-stimulated short-circuit current changes were inhibited by preincubation with piroxicam (10(-5) M), an inhibitor of arachidonic acid cyclooxygenase, suggesting prostaglandin formation as an intermediate step for cytokine stimulation of short-circuit current. In intact mucosal strips, interleukin 1 and 3 stimulated prostaglandin E2 release and elevated tissue 3',5'-cyclic adenosine monophosphate concentration. When prostaglandin E2 release from epithelial and subepithelial fractions of the mucosa by interleukin 1 was determined, increases were found only from the subepithelium. The secretory actions of cytokines appear to be mediated by arachidonic acid metabolites most likely produced by cells of the lamina propria and submucosa and may play a role in inflammatory processes in which intestinal secretion is enhanced.

Sixty Holstein bull calves were randomly assigned to one of three treatment groups following an initial 3-d colostrum feeding period. They were fed either whole cows' milk or ethanol-extracted or hexane-extracted soy flour in milk replacers to 6 wk of age. These products were used to identify possible causative factors associated with adverse responses to soybean in milk replacers. Average weight gains to 6 wk of age were 13.8, 7.3, and 2.8 kg and mortality was 0/20, 4/20, and 9/20 for calves fed milk, ethanol-extracted soy, and hexane-extracted soy, respectively. Heart rates (beats/min) were increased by the soy flours: 99.1 (ethanol extracted) and 116.3 (hexane extracted) versus 87.6 (milk). There was also an increased respiratory rate (breaths/min) with 67.6 and 61.1 versus 41.6 for the same treatment groups. Intradermal wheal growths verified an allergic sensitivity to the soybean products. Serum prostaglandin F2 alpha was 22% higher in the serum of calves fed the hexane-extracted soy milk replacer than in the serum of calves fed milk. Phenolic compounds in the soybean flour were implicated as possible causative factors in the adverse responses to the soybean milk replacers. Ethanol extraction of the soy flour was more effective than hexane extraction in removing phenolic compounds (2.19 vs. 1.00% phenolics).

This study determined if intracolonically applied prostaglandin E1 analogue (misoprostol) had a mucosal protective effect in rats with 4% acetic acid-induced colitis. The effects of misoprostol were compared with those of 5-aminosalicylic acid and betamethasone. A single application of 4% acetic acid induced an experimental colitis which was maximal at 2 days and showed spontaneous macroscopic and histologic healing by 12 days. Misoprostol (100 micrograms/kg), but not 5-aminosalicylic acid or betamethasone, administered 30 min before induction of colitis, provided macroscopic and histologic colonic mucosal protection but not protection of in vivo fluid absorption. The mucosal protective effect of misoprostol was time, dose, and diluent volume dependent. In the presence of misoprostol-induced colonic morphologic but not functional absorptive mucosal protection, in vitro unidirectional sodium and chloride flux measurements showed protection of theophylline-stimulated chloride secretion but not sodium absorption. Protection of in vivo colonic fluid absorption, in addition to morphologic protection, could be achieved when misoprostol was administered between 2 and 16 min before induction of colitis or when the highest dose (1000 micrograms/kg) of misoprostol was examined. We conclude that intracolonic misoprostol administration provides unique mucosal protective effects in experimental colitis.

Pretreatment with low-dose IL-1 has protective effects in animal models of inflammation or tissue injury, but the mechanisms of these protective effects are not established. To determine if prostaglandins are involved, we administered human recombinant IL-1 beta and measured rectal PGE2 production in rabbits with formalin-immune complex colitis. IL-1 beta (0.3 micrograms/kg) administered 24 h before induction of colitis increased PGE2 (231 +/- 36 to 1,299 +/- 572 pg/ml, P less than 0.01) and reduced subsequent inflammatory cell infiltration index (from 2.8 +/- 0.3 to 1.4 +/- 0.3, P less than 0.02) and edema (from 2.5 +/- 0.3 to 1.3 +/- 0.3, P less than 0.01) compared with vehicle-matched animals. Administration of ibuprofen (10 mg/kg i.v.) together with IL-1 beta prevented the stimulation of PGE2 and the reduction in inflammation. Colonic PGE2 production correlated inversely with subsequent severity of inflammation (P less than 0.02, r = -0.39) and edema (P less than 0.04, r = -0.35). IL-1-administration 30 min before induction of colitis did not affect the severity of inflammation. Similarly, pretreatment with a noninflammatory synthetic peptide (fragment 163-171) of human IL-1 beta, either 30 min or 24 h before colitis induction, did not reduce inflammation or increase prostaglandin synthesis. These data demonstrate that pretreatment with IL-1 beta 24 h before the induction of colitis reduces inflammation by a mechanism that requires prostaglandin synthesis.

Prostaglandins and thromboxanes are increased in human and experimental colitis, but the factors that regulate this enhanced production are unclear. The present studies evaluate the effects of the monokines, interleukin-1 alpha and beta on eicosanoid production in rabbit colon. In tissue incubations the peak dose response of eicosanoid release to human recombinant interleukin-1 is 50 ng/ml. Interleukin-1 alpha increases prostaglandin E2 (PGE2) by 4.5 +/- 1.9 ng/g tissue, 6-keto PGF1 alpha by 6.2 +/- 2.7 ng/g, and thromboxane B2 by 2.1 +/- 0.3 ng/g compared to placebo. In isolated rabbit colons perfused with Krebs' solution, 10-h infusion of interleukin-1 alpha (50 ng/ml) progressively increases production of PGE2, 6-keto PGF1 alpha, and thromboxane B2. Bolus injections of bradykinin increase production of PGE2, but not 6-keto PGF1 alpha and thromboxane B2, and these responses are markedly augmented by interleukin-1 alpha: at 10 h bradykinin-stimulated PGE2 production is 518 +/- 104 vs. 95 +/- 18 ng/5 min (p less than 0.005), 6-keto PGF1 alpha is 172 +/- 88 vs. 8 +/- 2 ng/5 min (p less than 0.02), and thromboxane B2 is 60 +/- 14 vs. 13 +/- 4 ng/5 min (p less than 0.02) for interleukin-treated colons vs. placebo-treated colons, respectively. The response is greater with interleukin-1 alpha than interleukin-1 beta. This study demonstrates that interleukin-1 stimulates prostaglandin and thromboxane production in normal colon tissue. These data are consistent with the concept that interleukin-1 production by inflammatory cells may augment prostaglandin and thromboxane production in colitis.