Prostanoids in human colonic mucosa: effects of inflammation on PGE(2) receptor expression.
Although the tissue concentration of PGE(2) is heightened 3-fold or more during mucosal inflammation, the cellular targets of prostanoids in human mucosa and the resulting changes in cell physiology have not been fully explored. We used a panel of immunoglobulin and mRNA probes in order to localize and quantitate the four member EP family of prostanoid receptors for binding PGE(2) to cells of histologically normal and inflamed human colonic mucosa, and then examined prostanoid-induced changes in mucosal lymphocyte function. Prostanoid receptors were selectively expressed on a limited number of human colonic mucosal cells; EP(4) alone was expressed on lamina propria mononuclear cells. Dual immunostaining in situ identified the CD3(+) T lymphocyte as a major EP(4) receptor-bearing cell in normal mucosa. Flow cytometry of isolated cells showed that 19.2% of lamina propria mononuclear cells were EP(4)(+), and almost 30% of these were CD3(+). In situ hybridization with digoxygenin-labeled RNA probes largely confirmed this localization. During inflammation, mucosal T lymphocytes showed a significant enhancement in EP(4) immunoreactive receptor protein. Computer-assisted densitometry of single cells demonstrated an increase in fluorescence intensity from 4.8 +/- 1.8 to 8.6 +/- 1.8 (p < 0.04). The effects of PGE(2) included a 35% reduction in T lymphocyte IL-2 secretion. COX 1(+) lamina propria cells nearly doubled in number during inflammation; expressed a T lymphocyte marker; but retained an unchanged quantity of immunoreactive COX 1 protein per cell. The number of newly appeared COX 2(+) lymphocytes remained <50% that of COX 1(+) cells. A major perturbation in the number and distribution of PGE(2) receptors and enzymes for prostanoid synthesis occurs in chronic inflammation of the colon, with consequences for mucosal T lymphocyte function.
Cosme
R
R
Departments of Internal Medicine and Pharmacology, University of Virginia Health Sciences Center, Charlottesville 22908, USA.
Lublin
D
D
Takafuji
V
V
Lynch
K
K
Roche
J K
JK
D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D003092:Colitis / Q000276:immunology*; D003106:Colon / Q000166:cytology / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; D015232:Dinoprostone / Q000378:metabolism* / Q000494:pharmacology; D015870:Gene Expression; D006801:Humans; D007376:Interleukin-2 / Q000378:metabolism; D007413:Intestinal Mucosa / Q000166:cytology / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D007419:Intestinal Secretions; D007527:Isoenzymes / Q000378:metabolism; D008565:Membrane Proteins; D008969:Molecular Sequence Data; D011451:Prostaglandin-Endoperoxide Synthases / Q000378:metabolism; D011453:Prostaglandins / Q000378:metabolism / Q000494:pharmacology; D012333:RNA, Messenger / Q000032:analysis; D011817:Rabbits; D018078:Receptors, Prostaglandin E / Q000096:biosynthesis* / Q000235:genetics; D058309:Receptors, Prostaglandin E, EP4 Subtype
D007376:Interleukin-2; D007527:Isoenzymes; D008565:Membrane Proteins; C545650:PTGER4 protein, human; D011453:Prostaglandins; D012333:RNA, Messenger; D018078:Receptors, Prostaglandin E; D058309:Receptors, Prostaglandin E, EP4 Subtype; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; C496511:PTGS1 protein, human; C496540:PTGS2 protein, human; D011451:Prostaglandin-Endoperoxide Synthases; D015232:Dinoprostone