Fabio Cominelli

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 Crohns 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, Crohns 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.

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.

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 hosts inflammatory response by counteracting the deleterious and possibly lethal effects of IL-1 produced during acute inflammation.

Inflammatory mediators of inflammatory bowel disease

Although much progress has been made in understanding the pathophysiology of inflammatory bowel disease, the precise etiology of Crohns disease and ulcerative colitis remains unknown. It has been suggested that the complex interactions between an initiating factor and the gut immune system are primarily responsible for the promotion and perpetuation of the chronic inflammation associated with this disease. Because of this, much attention has been focused on studying the role of immunocytes and their inflammatory mediators in the pathogenesis of inflammatory bowel disease. These inflammatory mediators include 1) proinflammatory cytokines (interleukin-1, tumor necrosis factor-α, and interleukin-8), 2) inhibitory cytokines (interleukin-1 receptor antagonist), 3) immunoregulatory cytokines (interleukin-2, interleukin-6, and interferon-γ), 4) lipid mediators (prostaglandin E2, leukotriene B4, and platelet activating factor), 5) oxygen free radicals, and 6) neuropeptides.

Effect of misoprostol on ibuprofen-induced renal dysfunction in patients with decompensated cirrhosis: Results of a double-blind placebo-controlled parallel group study

Effect of misoprostol on ibuprofen-induced renal dysfunction in patients with decompensated cirrhosis: results of a double-blind placebo-controlled parallel group study

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.

4-[5-(2,3-dihydroxyphenyl)pentyloxy]-2-hydroxy-3-propylbenzoic acid (Ro 24-0553): an orally active 5-lipoxygenase inhibitor with antiinflammatory activity

The chemical synthesis and pharmacological properties of 4-[5-(2,3-dihydroxyphenyl)pentyloxyl]-2-hydroxy-3-propylbenzoic acid (Ro 24-0553, 1), a novel 5-lipoxygenase (5-LO) inhibitor with in vivo activity appropriate for development as a therapy for inflammatory bowel disease, are described

Are oral prostaglandins effective in preventing nephrotoxicity from NSAIDs and cyclosporin

Prostaglandins are modulators of renal excretory function via alterations of intrarenal perfusion pressures and the distribution of blood flow. The predominant renal prostaglandins are prostacyclin (PGI2), prostaglandin E2 (PGE2) and PGF2α Medullary synthesis exceeds cortical synthesis five to ten fold, although PGI2 appears to be maximally produced in the cortex [1-3]. The regulation of basal prostaglandin production is still poorly understood, but renal injury readily augments output. This appears to be true independent of the mechanism of injury, whether by ischaemia, obstructive uropathy, toxic exposure or immunological disturbance [4,5]. Renal vasoconstriction markedly accelerates prostaglandin synthesis and release, and chronic renal damage is usually characterized by an elevation in renal vascular resistance. In addition, the infusion of exogenous vasoconstrictors such as angiotensin II or norepinephrine elicits release of the vasodilator PGE2 [4]. Under normal volume replete conditions renal function is to a very limited, if any extent dependent on endogenous prostaglandin synthesis. When maintenance of renal circulation is stressed by vasoconstricting hormones or by diminished circulating volume, then endogenous prostaglandin production becomes critically important in the maintenance of a normal renal blood flow (RBF) and glomerular filtration rate (GFR).