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Cyclooxygenase Inhibitors Monocytes Differential Regulation of Prostaglandin E2 and Thromboxane A 2 Production in Human Monocytes: Implications for the Use of Cyclooxygenase Inhibitors This information is current as of October 1, 2021. Peter S. Penglis, Leslie G. Cleland, Maryanne Demasi, Gillian E. Caughey and Michael J. James J Immunol 2000; 165:1605-1611; ; doi: 10.4049/jimmunol.165.3.1605 http://www.jimmunol.org/content/165/3/1605 Downloaded from References This article cites 31 articles, 16 of which you can access for free at: http://www.jimmunol.org/content/165/3/1605.full#ref-list-1 http://www.jimmunol.org/ Why The JI? Submit online. • Rapid Reviews! 30 days* from submission to initial decision • No Triage! Every submission reviewed by practicing scientists • Fast Publication! 4 weeks from acceptance to publication by guest on October 1, 2021 *average Subscription Information about subscribing to The Journal of Immunology is online at: http://jimmunol.org/subscription Permissions Submit copyright permission requests at: http://www.aai.org/About/Publications/JI/copyright.html Email Alerts Receive free email-alerts when new articles cite this article. Sign up at: http://jimmunol.org/alerts The Journal of Immunology is published twice each month by The American Association of Immunologists, Inc., 1451 Rockville Pike, Suite 650, Rockville, MD 20852 Copyright © 2000 by The American Association of Immunologists All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. Differential Regulation of Prostaglandin E2 and Thromboxane A2 Production in Human Monocytes: Implications for the Use of Cyclooxygenase Inhibitors1 Peter S. Penglis,2 Leslie G. Cleland, Maryanne Demasi, Gillian E. Caughey, and Michael J. James There is an autocrine relationship between eicosanoid and cytokine synthesis, with the ratio of prostaglandin E2 (PGE2)/throm- boxane A2 (TXA2) being one of the determinants of the level of cytokine synthesis. In monocytes, cyclooxygenase type 1 (COX-1) activity appears to favor TXA2 production and COX-2 activity appears to favor PGE2 production. This has led to speculation regarding possible linkage of COX isozymes with PGE and TXA synthase. We have studied the kinetics of PGE2 and TXA2 synthesis under conditions that rely on COX-1 or -2 activity. With small amounts of endogenously generated prostaglandin H2 Downloaded from (PGH2), TXA2 synthesis was greater than PGE2. With greater amounts of endogenously generated PGH2, PGE2 synthesis was greater than TXA2. Also, TXA synthase was saturated at lower substrate concentrations than PGE synthase. This pattern was observed irrespective of whether PGH2 was produced by COX-1 or COX-2 or whether it was added directly. Furthermore, the inhibition of eicosanoid production by the action of nonsteroidal anti-inflammatory drugs or by the prevention of COX-2 induction with the p38 mitogen-activated protein kinase inhibitor SKF86002 was greater for PGE2 than for TXA2. It is proposed that different kinetics of PGE synthase and TXA synthase account for the patterns of production of these eicosanoids in monocytes under a variety of experimental conditions. These properties provide an alternative explanation to notional linkage or compart- http://www.jimmunol.org/ mentalization of COX-1 or -2 with the respective terminal synthases and that therapeutically induced changes in eicosanoid ratios toward predominance of TXA2 may have unwanted effects in long-term anti-inflammatory and anti-arthritic therapy. The Journal of Immunology, 2000, 165: 1605–1611. 3 rostaglandin E2 (PGE2) and thromboxane A2 (TXA2) are tive terminal synthases engage PGH2 and convert it to their eico- members of a family of 20-carbon fatty acid derivatives, sanoid products. P known collectively as eicosanoids. They are involved in However, recent reports have suggested that the activities of normal physiology and in inflammatory responses (1, 2). Release the different COX isozymes, constitutive COX-1 and inducible by guest on October 1, 2021 of arachidonic acid (AA) from membrane phospholipids provides COX-2, may be associated with different eicosanoids end prod- the primary substrate for eicosanoid synthesis (3, 4). AA is oxy- ucts. For example, it was demonstrated in rat peritoneal cells genated by the cyclooxygenase (COX) enzyme, which synthesizes that COX-2 activity favored PGE2 or prostacyclin production, first the transient intermediate prostaglandin G2 and then the un- whereas COX-1 activity favored TXA2 production (7, 8). To stable endoperoxide, prostaglandin H2 (PGH2) (5). PGH2,asthe explain these findings, the authors suggested compartmental- substrate for PGE synthase and TXA synthase, is the common ization or functional linkage of COX isozymes with the differ- precursor for all of the two-series prostaglandins. Because PGE2 ent terminal synthases (7) or the induction of PGE synthase in and TXA2 have opposing autocrine effects on cytokine production conjunction with COX-2 (8, 9). (6), it is important to understand how the ratio of these two me- Confirming these observations, we observed in the present study diators is regulated. Because PGE2 and TXA2 arise from the com- that in the presence of COX-1 alone, TXA2 was produced in ex- mon intermediate PGH2, their relative rates of production by a cell cess of PGE2, whereas after the induction of COX-2 the eicosanoid should depend on the relative efficiencies with which the respec- ratio was reversed. However, these conditions involve substantial differences in availability of PGH2. Therefore, we examined to what extent differences in the kinetic properties of the terminal synthases may explain the differences in the ratios of PGE2 and Rheumatology Unit, Royal Adelaide Hospital, Adelaide, Australia TXA2, which had been attributed to the respective COX isozymes. Received for publication January 5, 2000. Accepted for publication May 17, 2000. The costs of publication of this article were defrayed in part by the payment of page Materials and Methods charges. This article must therefore be hereby marked advertisement in accordance Materials with 18 U.S.C. Section 1734 solely to indicate this fact. 1 This work was supported by a grant from the National Health and Medical Research Materials were obtained from the following sources: AA and carboxyhep- Council of Australia (to M.J.J. and L.G.C.) and by the Dawes Scholarship scheme of tyl-imidazole (CI) (Sapphire Bioscience, Sydney, Australia); NS-398, rab- the Royal Adelaide Hospital (to P.S.P.). bit PGE2 anti-serum, and COX-1 and -2 Abs (Cayman Chemical, Ann 2 Address correspondence and reprint requests to Dr. Peter S. Penglis, Rheumatology Arbor, MI); PGH2 (Calbiochem-Novabiochem, La Jolla, CA); TXA2, Unit, Royal Adelaide Hospital, North Terrace, Adelaide, SA, Australia. E-mail ad- thromboxane B2 (TXB2) antiserum prepared from a rabbit immunized with dress: [email protected] thromboxane conjugated to human thyroglobulin as used in previous stud- 3 Abbreviations used in this paper: PGE , prostaglandin E ; TXA , thromboxane A ; ies (10); pyrogen-free Lymphoprep (Nycomed, Oslo, Norway); E-Toxa- 2 2 2 2 Clean, LPS, zymosan, DTT, and glutathione (Sigma, St. Louis, MO); {5- AA, arachidonic acid; COX, cyclooxygenase; PGH2, prostaglandin H2; CI, carboxy- heptyl-imidazole; TXB , thromboxane B ; STZ, serum-treated zymosan; NSAID, (4-pyridyl)-6 (4-fluorophenyl)-2,3-dihydroimidazo (2, 1-b) thiazole} 2 2 ␣ nonsteroidal anti-inflammatory drug. (SKF86002) (Calbiochem, San Diego, CA); 1 ,25-dihydroxyvitamin D3 Copyright © 2000 by The American Association of Immunologists 0022-1767/00/$02.00 1606 DIFFERENTIAL REGULATION OF EICOSANOID SYNTHESIS IN MONOCYTES (Biomol, Plymouth Meeting, PA); Trans-blot transfer membranes (Bio- Rad, North Ryde, Australia); and peroxidase-labeled donkey anti-rabbit Abs and enhanced chemiluminescence Western blotting analysis system (Amersham, Little Chalfont, England). Serum-treated zymosan (STZ) was prepared by boiling zymosan for 1 h and then incubating it with freshly prepared human serum for 24 h before washing and resuspension in PBS. Monocyte isolation Buffy coats were obtained from the Red Cross Blood Center (Adelaide, South Australia). Mononuclear cells were separated by centrifugation (800 ϫ g, 30 min) on pyrogen-free Lymphoprep. Monocytes were then isolated by countercurrent centrifugal elutriation (JE-5B Elutriation Sys- tem; Beckman, Palo Alto, CA). Purity of monocytes was confirmed at Ͼ85% by FACS analysis, and contaminant cells were nearly all lympho- cytes. All glassware was washed with E-Toxa-Clean to minimize LPS contamination. U937 cells Cells were cultured in RPMI 1640 supplemented with 10% FCS and penicillin/gentamicin. Experimental procedure Downloaded from Elutriated monocytes or U937 cells were resuspended at 2 ϫ 106 cells/ml in RPMI 1640 supplemented with low-LPS 10% FCS and penicillin/gen- tamicin. Monocytes were stimulated with LPS (20 ng/ml final concentra- tion) overnight in nonadherent teflon Minisorp tubes (Nunc, Copenhagen, Denmark) in a total incubation volume of 1 ml at 37°C with 5% CO2. U937 ␣ ϫ cells were incubated overnight with 1 ,25-dihydroxyvitamin D3 (9.8 10Ϫ9 M) to promote monocytoid differentiation and then were stimulated http://www.jimmunol.org/ with STZ (100 ng/ml final concentration) overnight or for the indicated times. After the incubation periods, cells were washed two times in RPMI and then resuspended in RPMI (no FCS) at 2 ϫ 106 cells/ml. AA was added and cells were incubated at 37°C with 5% CO2 for 4 min, which was FIGURE 1. PGE2 and TXA2 production in elutriated human
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