Inflammatory bowel disease: short- and long-term treatments.
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Adjuvants, Immunologic↗
Biomedical subjects
F Cominelli
Publications and source records attributed to F Cominelli.
Interleukin-1 receptor antagonist: a "novel" acute phase protein with antiinflammatory activities.
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Anti-Inflammatory Agents↗
A new syndrome of Crohn's disease and pachydermoperiostosis in a family.
Few syndromic associations with Crohn's disease are described. The aim of this study was to characterize a new syndrome of Crohn's disease associated with pachydermoperiostosis in 3 brothers. Three probands, 6 siblings, both parents, 20 of 21 third-generation relatives, and 9 spousal controls were evaluated. Serological evaluation for antineutrophil cytoplasmic antibodies and human leukocyte antigens as well as genetic testing for tumor necrosis factor microsatellites, intercellular adhesion molecule 1 polymorphisms, the interleukin 1 receptor antagonist gene, and the interleukin 1 beta gene were performed. Only the 3 probands were affected and developed pachydermoperiostosis between ages 14 and 17 years. Pachydermoperiostosis preceded Crohn's ileocolitis by 6 and 20 years in two probands, excluding secondary hypertrophic osteoarthropathy. Two probands were antineutrophil cytoplasmic antibody positive vs. 1 of 27 unaffected relatives (P < 0.001, chi 2). Haplotypes for human leukocyte antigen and tumor necrosis factor microsatellites were discordant. The probands' generation was homozygous for the common allele 1 of the interleukin 1 receptor antagonist and interleukin 1 beta genes. Two probands carried a rare polymorphism of the intercellular adhesion molecule 1 gene. A new syndrome of Crohn's disease and pachydermoperiostosis associated with antineutrophil cytoplasmic antibodies is described. Inheritance is most likely autosomal recessive by pedigree. No clear association was found between this syndrome and the gene regions evaluated.
Adolescent↗
Hyponatremia of cirrhosis: role of vasopressin and decreased 'effective' plasma volume.
BACKGROUND: The mechanism(s) of hyponatremia of cirrhosis is not completely clarified. Although increased vasopressin activity has been proposed in some studies, there have been reports disputing its role in the pathogenesis of profound hyponatremia in patients with decompensated liver disease. Methodologic flaws and lack of correlation with indices of circulatory dysfunction may have contributed to these discrepancies. The aims of the present study were to measure levels of vasopressin both in plasma and in urine and to correlate them with the volume-dependent hormonal systems of plasma renin activity (PRA) and atrial natriuretic factor (ANF). METHODS: Plasma vasopressin, ANF, and PRA were measured by radioimmunoassay in 19 patients with cirrhosis, ascites, and severe hyponatremia (mean serum sodium, 121.8 mmol/l) and 11 patients with cirrhosis and normal serum sodium (mean, 137.6 mmol/l). Vasopressin levels were also assessed by radioimmunoassay in urine. RESULTS: Patients with hyponatremia had higher plasma and urine vasopressin levels than patients with normal serum sodium concentrations (plasma, 2.9 versus 1.0 pg/ml, P = 0.0009; urine, 38.3 versus 12.3 ng/g creatinine, P = 0.0008). PRA was higher (4.8 versus 1.0 ng/ml/h, P = 0.0004) and plasma ANF lower (111.1 versus 148.7 pg/ml, P = 0.01) in patients with hyponatremia. CONCLUSIONS: These results indicate that plasma and urine vasopressin levels are inappropriately increased in patients with cirrhosis and severe hyponatremia. The concomitant increase of PRA and decrease of plasma ANF suggest that decreased 'effective' plasma volume generates nonosmotic stimuli for vasopressin hypersecretion in these patients.
Adult↗
Interleukin-1 and interleukin-1 receptor antagonist in inflammatory bowel disease.
Ulcerative colitis (UC) and Crohn's disease (CD) are immunologically mediated disorders characterized by a chronic, relapsing inflammatory response. Elevation of several cytokines, with important immunoregulatory and proinflammatory activities have been demonstrated during active inflammatory bowel disease (IBD). These cytokines, including interleukin-1 (IL-1), IL-6, IL-8 and GM-CSF, may play an important role in the initiation and amplification of the inflammatory response leading to intestinal injury. There is increasing evidence that IL-1 is activated early in the cascade of events leading to inflammation. Therefore, IL-1 has been implicated as a primary target for therapeutic intervention for the treatment of several inflammatory diseases, including IBD. In addition, a mucosal imbalance of intestinal IL-1 and IL-1ra is present in patients with IBD, suggesting that insufficient production of endogenous IL-1ra may contribute to the pathogenesis of chronic gut inflammation. Preliminary studies examining the association between newly described polymorphisms in the IL-1 gene cluster and IBD have provided new insight into the genetic predisposition to UC. This article will review current progress in understanding the role of Il-1 and Il-1ra in IBD, as well as discuss recently described polymorphisms in the Il-1 gene cluster and their association with UC and CD.
Animals↗
Mucosal imbalance of IL-1 and IL-1 receptor antagonist in inflammatory bowel disease. A novel mechanism of chronic intestinal inflammation.
The etiology and pathogenesis of inflammatory bowel disease (IBD) are unknown. Increasing evidence supports the theory that chronic IBD is the result of dysfunctional immunoregulation manifested by an inappropriate production of mucosal cytokines. The aim of the present study was to test the hypothesis that a specific mucosal imbalance of IL-1 and IL-1 receptor antagonist (IL-1ra) production plays an important role in the perpetuation and chronicity of intestinal inflammation. Total IL-1, IL-1ra, and the IL-1ra/IL-1 ratio were measured in freshly isolated intestinal mucosal cells, as well as in mucosal biopsies obtained from control, Crohn's disease, and ulcerative colitis patients. IL-1 alpha, IL-1 beta, and IL-1 ra were measured by specific non-cross-reacting radioimmunoassays and ELISA. A markedly significant decrease in the intestinal mucosal IL-1ra/IL-1 ratio was found in both Crohn's disease and ulcerative colitis patients when compared with control subjects (p < 0.01). The IL-1ra/IL-1 ratio correlated closely with the clinical severity of disease (r = -0.7846, p < 0.001). Furthermore, the observed decrease in the IL-1ra/IL-1 ratio was specific for IBD because a decreased IL-1ra/IL-1 ratio was not found in patients with self-limiting colitis. These results support the hypothesis that an imbalance between IL-1 and IL-1ra production is of pathogenic importance in chronic inflammatory diseases, including IBD.
Adolescent↗
Anti-inflammatory effects of CGP 47969A, a novel inhibitor of proinflammatory cytokine synthesis, in rabbit immune colitis.
BACKGROUND & AIMS: Proinflammatory cytokines such as interleukin (IL) 1, IL-8, and tumor necrosis factor (TNF) have been implicated as primary mediators of intestinal inflammation. The aim of the present study was to determine the effects of a novel cytokine antagonist (CGP 47969A) in a rabbit model of acute colitis. METHODS: Colitis was induced using the formalin-immune complex technique. Animals were pretreated intrarectally with CGP 47969A (30, 10, or 3 mg/kg), hydrocortisone (0.8 mg/kg), or vehicle (4 mL saline) 2 hours before the induction of colitis and twice daily thereafter until death 48 hours after the induction of colitis. The severity of inflammation of colonic tissue was assessed using histological analysis and myeloperoxidase activity assay, and IL-1 alpha, IL-8, TNF-alpha, and IL-1 receptor antagonist levels were determined. RESULTS: Compared with vehicle, CGP 47969A (10 mg/kg) significantly reduced the acute inflammatory index by 58%, edema by 67%, necrosis by 99%, and myeloperoxidase activity by 49% (all P < 0.02) with efficacy similar to that of steroids. These effects were associated with a significant inhibition of colonic IL-1 alpha and IL-8 by 56% and 90%, respectively (p < 0.01). CONCLUSIONS: Administration of CGP 47969A reduces inflammation and tissue damage in rabbit immune complex colitis through mechanisms involving the inhibition of mucosal proinflammatory cytokines.
Animals↗
A randomized double-blind comparison of placebo, etodolac, and naproxen on gastrointestinal injury and prostaglandin production.
BACKGROUND: NSAIDs frequently cause gastrointestinal injury and increase the risk of ulcer complications. We compared an NSAID suggested to cause less gastric injury (etodolac) with a standard NSAID (naproxen) and a placebo in a 4-week double-blind trial assessing the effects on gastroduodenal injury, symptoms, and prostaglandin production in healthy volunteers. METHODS: Fifty-two healthy volunteers not taking NSAIDs, alcohol, antibiotics, bismuth, or anti-ulcer drugs: placebo, etodolac 400 mg, or naproxen 500 mg b.i.d. for 4 weeks. Endoscopies with biopsies were repeated at weeks 1 and 4. The number and dimensions of ulcers and erosions were recorded to quantitate injury. RESULTS: At week 1 the mean number and area of gastric ulcers per subject were greater with naproxen than placebo or etodolac (area: naproxen, 7.4 mm2; placebo, 0.6 mm2, p = 0.02 vs naproxen; etodolac, 2.1 mm2, p = 0.06 vs naproxen). Ulcer scores at week 4 were low and comparable in the three groups. The mean number and area of gastric erosions per subject were greatest with naproxen at both weeks 1 and 4 (week 4 area: naproxen, 58.3 mm2; placebo, 29.0 mm2; etodolac, 13.9 mm2, p < 0.02, naproxen vs placebo and vs etodolac). Placebo injury was presumably due to biopsies at prior endoscopy. Gastric mucosal prostaglandin E2 production did not change significantly from baseline after 1 or 4 weeks of treatment with placebo or etodolac, but did decrease significantly with naproxen (week 0, 1689; week 1, 479; week 4, 577 pg/mg protein). Gastrointestinal symptoms were present in only 1 (5%) of 20 visits in which endoscopy showed no erosions or ulcers vs 21 (26%) of 82 visits in which a mucosal defect was identified (p = 0.666). CONCLUSION: Gastric injury with 4 weeks of etodolac is comparable to that seen with placebo and significantly less than that occurring with naproxen, presumably due to the fact that etodolac does not suppress gastric mucosal prostaglandin production, whereas naproxen leads to a significant reduction.
Adult↗
Interaction of NSAIDs and Helicobacter pylori on gastrointestinal injury and prostaglandin production: a controlled double-blind trial.
BACKGROUND: H. pylori and nonsteroidal anti-inflammatory drugs (NSAIDs) are major causes of gastroduodenal injury in man. We assessed the effect of daily NSAID ingestion on gastric histology and the interaction of H. pylori infection and NSAID ingestion on gross and histological injury and prostaglandin production. METHODS: Fifty-two healthy volunteers with normal baseline endoscopy were randomly assigned to receive identical-appearing naproxen 500 mg b.d., etodolac 400 mg b.d., or placebo b.d. for 4 weeks. The number and size of all erosions and ulcers were recorded by endoscopy at weeks 1 and 4. Biopsies taken at baseline, week 1 and week 4 were assessed for H. pylori, histology and gastric prostaglandin E2 production. RESULTS: No significant changes occurred with treatment in any histological feature in the three study groups or in H. pylori positive or negative subsets. Antral inflammation scores (scale, 0-6) for the NSAID group were: week 0--1.2 +/- 0.3; week 1--1.1 +/- 0.3; week 4--1.3 +/- 0.3; findings of 'chemical gastritis' were not seen. No significant difference in gross gastroduodenal injury (number or total surface area of ulcers or erosions) was seen between H. pylori positive and negative subjects in the three groups at week 1 or 4. Baseline prostaglandin E2 production was significantly higher in H. pylori positive subjects (2398 +/- 400 vs. 1064 +/- 255 pg/mg protein) and decreased significantly with 1 week of naproxen in H. pylori positive and negative subjects. CONCLUSIONS: NSAID ingestion does not cause diffuse histological injury. Any diffuse histological injury in the gastric mucosa is related to the presence of H. pylori, and this H. pylori-associated gastritis is not altered by NSAID ingestion. Furthermore, the development of gross gastroduodenal damage with 4 weeks of NSAID use is not influenced by underlying H. pylori infection.
Adolescent↗
Rabbit interleukin-1 receptor antagonist. Cloning, expression, functional characterization, and regulation during intestinal inflammation.
Genomic and cDNA clones for rabbit interleukin-1 receptor antagonist (IL-1ra) were isolate based on homology with the human, mouse, and rat IL-1ra gene. A partial genomic clone, obtained by screening a rabbit genomic library, contained coding sequences for the carboxyl-terminal 108 amino acids of rabbit IL-1ra. Two classes of cDNA for rabbit IL-1ra were obtained using RNA from inflamed rabbit colon tissue. One class of cDNA coded for a secreted form of IL-1ra, whereas the other coded for a putative intracellular form of rabbit IL-1ra. The latter form is similar to that isolated from human epithelial cells. A partially synthetic rabbit IL-1ra gene was constructed and expressed in Escherichia coli. The recombinant rabbit IL-1ra was purified to homogeneity by ion exchange chromatography. Its affinity was similar to that of human IL-1ra for the human and mouse type I IL-1 receptor. From the cDNA clone and the purified recombinant protein, specific probes were developed for measuring levels of rabbit IL-1ra mRNA and protein in normal and inflamed rabbit tissues. Unlike IL-1 alpha and IL-1 beta, IL-1RA mRNA and protein were present at detectable levels in normal rabbit colon. During the development of an experimental formalin-immune complex colitis, rabbit IL-1 alpha showed a dramatic increase in tissue levels, consistent with previous results; IL-1ra also increased 3-4-fold. Treatment of colitis rabbits with corticosteroids significantly suppressed neutrophil infiltration, corticosteroid treatment suppressed IL-1ra but not IL-1 alpha mRNA steady-state levels. Our observations demonstrate that IL-1 and IL-1ra synthesis is differentially regulated in healthy and inflamed intestinal tissue.
Amino Acid Sequence↗
Neutralization of endogenous IL-1 receptor antagonist exacerbates and prolongs inflammation in rabbit immune colitis.
Administration of exogenous interleukin-1 receptor antagonist (IL-1ra) is effective in reducing the severity of disease in animal models of acute inflammation. However, the function of endogenous IL-1ra in this process, is not yet known. We investigated the pathophysiological role of IL-1ra in a rabbit model of formalin-immune complex colitis. This model has previously been shown to be IL-1 mediated and a reduction in disease severity is observed with exogenous IL-1ra treatment. Colonic IL-1ra was found to be elevated subsequent to IL-1, and exceeded IL-1 levels 10-fold. Peak levels of IL-1ra preceded both the resolution of colitis and a significant decrease in IL-1 production. Administration of specific neutralizing antibodies against rabbit IL-1ra increased mortality and prolonged intestinal inflammatory responses. A significant increase in IL-1 alpha colonic tissue levels was also measured as a result of exogenous anti-IL-1ra treatment. These studies are the first demonstration that endogenous IL-1ra may play an important role in regulating the host's inflammatory response by counteracting the deleterious and possibly lethal effects of IL-1 produced during acute inflammation.
Animals↗
Localization of intestinal interleukin 1 activity and protein and gene expression to lamina propria cells.
BACKGROUND: Interleukin 1 (IL-1) is a key mediator of bowel inflammation, but there is limited knowledge about the amount and site of production of this cytokine in the gastrointestinal tract under physiological or pathological conditions. METHODS: Epithelial and lamina propria mononuclear cells were isolated from control, and Crohn's disease- and ulcerative colitis-involved mucosa to investigate the capacity of these cells to generate IL-1 bioactivity, IL-1 alpha and IL-1 beta immunoreactivity, and gene expression. RESULTS: Control lamina propria mononuclear cells produced substantial amounts of IL-1 alpha and IL-1 beta, which increased dramatically when inflammatory bowel disease cells were used. Epithelial cells from control, Crohn's disease, and ulcerative colitis intestine displayed no IL-1 bioactivity or immunoreactivity. Lamina propria mononuclear cells contained moderate to large quantities of IL-1 alpha and IL-1 beta messenger RNA (mRNA), respectively, whereas epithelial cells had none. The absence of IL-1 transcripts in epithelial cells was selective, because mRNA for HLA-DR antigens was present in control and inflammatory bowel disease cells. CONCLUSIONS: In normal and inflamed human intestine there is a distinct compartmentalization of IL-1, as mononuclear but not epithelial cells generate this cytokine. The high levels of IL-1 in inflammatory bowel disease may explain several of its local and systemic manifestations, and blockade by specific antagonists could have important therapeutic effects.
Adolescent↗
Recombinant interleukin-1 receptor antagonist blocks the proinflammatory activity of endogenous interleukin-1 in rabbit immune colitis.
The effects of human recombinant interleukin-1 receptor antagonist (IL-1ra) on inflammation, tissue damage, and production of inflammatory mediators in rabbit formalin-immune complex colitis were examined. Treatment of rabbits with intravenous administration of IL-1ra before and periodically throughout the first 43 hours after the induction of colitis (total 7 doses) suppressed inflammation and tissue damage in a dose-related manner. Maximum inhibition of inflammatory index (from 3.0 +/- 0.3 to 0.8 +/- 0.3, P less than 0.001), edema (from 2.3 +/- 0.2 to 0.6 +/- 0.2, P less than 0.001), percent of mucosal necrosis (from 44% +/- 7% to 7% +/- 3%, P less than 0.02) and myeloperoxidase (MPO) activity (from 4.9 +/- 1.0 U/g to 1.0 +/- 0.3 U/g, P less than 0.001) occurred with the dose of 5 mg/kg. Colonic prostaglandin E2 (PGE2) and leukotriene B4 (LTB4) production, measured in rectal dialysates by specific radioimmunoassays, was also dose dependently suppressed (from 1124 +/- 319 pg/mL to 190 +/- 75 pg/mL, P less than 0.001 and 568 +/- 192 pg/mL to 92 +/- 51 pg/mL, P less than 0.001, respectively, at 5 mg/kg). In contrast, colonic IL-1 alpha tissue levels measured by a specific radioimmunoassay after tissue extraction were similar in all groups. When only two doses of IL-1ra, 10 minutes before and 3 hours after the induction of colitis were given, there was no longer an inhibitory effect on inflammation or production of inflammatory mediators. However, delaying the initial IL-1ra treatment 3 hours after the induction of colitis (total 6 doses) was effective in reducing inflammatory index (by 60%), MPO activity (by 79%), PGE2 (by 62%), and LTB4 (by 72%) whereas colonic IL-1 alpha levels were unchanged compared with vehicle-treated animals. These studies show the ability of human recombinant IL-1 receptor antagonist to suppress the proinflammatory activity of IL-1 produced in the colon during the induction and progression of rabbit immune complex colitis.
Animals↗
Effect of cell culture on rabbit colonic smooth muscle bradykinin receptors.
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.
Animals↗
An abnormal rate of actin myosin cross-bridge cycling in colonic smooth muscle associated with experimental colitis.
Previous studies showed that colonic smooth muscle develops less contractile force to neurohumoral stimulation when associated with mucosal inflammation. This study evaluated 1) the Ca2+ dependence for colonic smooth muscle contraction, 2) the maximum velocity of muscle shortening (Vmax), and 3) changes in 20-kDa myosin light-chain (MLC) phosphorylation in distal circular colonic muscle from healthy rabbits and from rabbits with experimental colitis, induced by Formalin and immune complexes. The isometric tension of unskinned muscle stimulated with bethanechol or KCl was less (P less than 0.05) in animals with colitis compared with the control group. In saponin-skinned muscle, the amplitude of the maximal tension at [Ca2+] of 3 x 10(-7) M was decreased (P less than 0.05) in colitis animals (4.3 +/- 0.9 x 10(4) N/m2, n = 7) compared with healthy animals (10.5 +/- 2.4 x 10(4) N/m2, n = 6). However, the ED50 for Ca2+ stimulation was similar (P greater than 0.05) in both groups. When MLC was thiophosphorylated with ATP gamma S, the tension development was decreased in colitis (2.1 +/- 0.3 x 10(4) N/m2, n = 5; P less than 0.01) compared with normals (5.0 +/- 1.4 x 10(4) N/m2, n = 5). In healthy animals, phosphorylation of 20-kDa MLC increased rapidly to 51.2 +/- 3.1% within 15 s after stimulation and subsequently declined to 19.0 +/- 2.1% at 5 min. Vmax was maximal (0.14 Lo/s) 13 s after stimulation and declined before maximal active isometric stress. In colitis animals, the 20-kDa MLC phosphorylation (P less than 0.05) and the Vmax (P less than 0.01) were decreased.(ABSTRACT TRUNCATED AT 250 WORDS)
Actins↗
Calcitonin gene-related peptide and substance P decrease in the rabbit colon during colitis. A time study.
The sensory neuropeptides, substance P and calcitonin gene-related peptide, have been implicated in inflammatory reactions in several tissues. An immune-complex model of colitis was used in rabbits to determine the colonic content (nmol/g protein) of immunoreactive substance P and calcitonin gene-related peptide at various times after induction of inflammation to assess changes in these neuropeptides during the inflammatory response. Calcitonin gene-related peptide content was decreased by 66% 4 hours after induction of inflammation and reached a maximum of 80% at 48 hours. The substance P content was decreased at 8 hours, with a maximum decrease of 64% at 48 hours. Substance P decrease was detected in the muscle layer. The amounts of substance P in the mucosal/submucosal layer extracts were too low to allow accurate measurements. Calcitonin gene-related peptide decreased both in the muscle and the mucosal-submucosal layers. Immunohistochemical analysis showed that calcitonin gene-related peptide and substance P innervation patterns were comparable in normal and inflamed colon, even though there appeared to be a decrease in density and intensity of the staining, particularly for calcitonin gene-related peptide at 48 hours. The early decrease of calcitonin gene-related peptide and substance P during the time course of colitis might be due to release from nerve terminals of the gut during the inflammatory response. The profound changes in colonic calcitonin gene-related peptide and substance P content during colitis may have important implications during inflammation and subsequent tissue repair and may also lead to disturbances in gut motility.
Animals↗
Detection of interleukin 1 alpha and 1 beta in rabbit tissues during endotoxemia using sensitive radioimmunoassays.
Interleukin 1 (IL-1) is a primary mediator of a wide variety of immunologic and inflammatory responses, including reactions to microbial infections. To study this cytokine in an animal model, we have developed specific and sensitive radioimmunoassays for the quantitation of rabbit IL-1 alpha and IL-1 beta. The sensitivity (limit of detection at 95% confidence level) of our assay for IL-1 alpha and 1 beta was 20-40 and 40-80 pg/ml, respectively. Recovery of IL-1 from tissues ranged from 75 to 107%, with a mean of 95% for IL-1 alpha and 89% (range 19-98) for IL-1 beta. We employed these assays in in vivo and in vitro studies. In an in vivo model, we measured the amount of rabbit IL-1 alpha and 1 beta protein present in brain, kidney, liver, lung, muscle, and spleen at various times after the injection of endotoxin. IL-1 was found in all tissues studied but largely in the spleen; IL-1 levels were transient, reaching peak levels by 4 h after injection of endotoxin and rapidly decreasing to low levels by 24 h. In similar in vitro studies, IL-1 alpha levels reached peak elevation 6 h after addition of endotoxin, whereas IL-1 beta was maximal at 24 h. IL-1 alpha was detected in all tissues; IL-1 beta was observed primarily in lung, kidney, and spleen. These studies establish the presence of IL-1 in various tissues during endotoxemia.
Animals↗
Interleukin 1 suppresses inflammation in rabbit colitis. Mediation by endogenous prostaglandins.
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.
Animals↗