Potential role for interleukin-1 in the pathophysiology of ulcerative colitis.
1. Biopsies of colonic mucosa from patients with ulcerative colitis liberated more interleukin-1 beta, prostaglandin E2, leukotriene C4 and platelet-activating factor into the medium in which they were cultured than biopsies from patients with irritable bowel syndrome and histologically normal mucosa. 2. Addition of interleukin-1 stimulated release of greater quantities of all these inflammatory mediators, including interleukin-1 itself, from inflamed and normal mucosa. 3. Blockade of cyclo-oxygenase with indomethacin or of lipoxygenase with ICI 207968 or of phospholipase A2 with mepacrine inhibited release of prostaglandin E2 or leukotriene C4 or both of these plus platelet-activating factor, respectively. 4. Interleukin-1 stimulated the short-circuit current across isolated rat colonic mucosa mounted in flux chambers in a dose-dependent manner (Km 2 x 10(-11) mol/l). This stimulation was markedly inhibited by the removal of chloride from the bathing media. 5. Indomethacin or ICI 207968 inhibited the short-circuit current response to interleukin-1 and a combination of these antagonists produced a greater inhibition. Mepacrine caused an even greater inhibition whereas tetrodotoxin plus mepacrine inhibited the current completely. 6. These data indicate that interleukin-1, released in excess from inflamed colonic mucosa, stimulates the release of a range of inflammatory mediators as well as of more interleukin-1. It probably acts by stimulating phospholipase A2 in inflammatory cells, probably lymphocytes, and can do so in normal and inflamed mucosa. Since, in rat colonic mucosa it stimulated an electrical response in very low concentrations, it is feasible that it is involved in the chloride secretion, and hence the diarrhoea, which may occur in inflammatory reactions.(ABSTRACT TRUNCATED AT 250 WORDS)
University Department of Medicine, Hope Hospital, Salford, U.K.
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Wardle
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Turnberg
D000328:Adult; D000818:Animals; D003093:Colitis, Ulcerative / Q000378:metabolism*; D003106:Colon / Q000187:drug effects / Q000378:metabolism*; D003470:Culture Media; D046508:Culture Techniques; D015232:Dinoprostone / Q000096:biosynthesis; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D007375:Interleukin-1 / Q000096:biosynthesis / Q000494:pharmacology / Q000502:physiology*; D007413:Intestinal Mucosa / Q000378:metabolism*; D017997:Leukotriene C4 / Q000096:biosynthesis; D008297:Male; D008875:Middle Aged; D010741:Phospholipases A / Q000037:antagonists & inhibitors; D054467:Phospholipases A2; D010972:Platelet Activating Factor / Q000096:biosynthesis; D011796:Quinacrine / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley
D003470:Culture Media; D007375:Interleukin-1; D010972:Platelet Activating Factor; D017997:Leukotriene C4; D010741:Phospholipases A; D054467:Phospholipases A2; D011796:Quinacrine; D015232:Dinoprostone